CDK-inhibitory pyrimidines, their production and use as pharmaceutical agents

ABSTRACT

This invention relates to pyrimidine derivatives of general formula I  
                 
 
     in which R 1 , R 2 , X, A and B have the meanings that are contained in the description, as inhibitors of the cyclin-dependent kinases, their production as well as their use as medications for treating various diseases.

[0001] This invention relates to pyrimidine derivatives, theirproduction as well as their use as medications for treating variousdiseases.

[0002] The CDKs (cyclin-dependent kinase) is an enzyme family that playsan important role in the regulation of the cell cycle and thus is anespecially advantageous target for the development of small inhibitorymolecules. Selective inhibitors of the CDKs can be used for treatingcancer or other diseases that cause disruptions of cell proliferation.

[0003] Pyrimidines and analogs are already described as activeingredients, such as, for example, the 2-anilino-pyrimidines asfungicides (DE 4029650) or substituted pyrimidine derivatives fortreating neurological or neurodegenerative diseases (WO 99/19305). AsCDK-inhibitors, the most varied pyrimidine derivatives are described,for example bis(anilino)-pyrimidine derivatives (WO 00/12486),2-amino-4-substituted pyrimidines (WO 01/14375), purines (WO 99/02162),5-cyano-pyrimidines (WO 02/04429), anilinopyrimidines (WO 00/12486) and2-hydroxy-3-N,N-dimethylaminopropoxy-pyrimidines (WO 00/39101).

[0004] The object of this invention is to provide compounds that havebetter properties than the inhibitors that are already known. Thesubstances that are described here are more effective, since theyalready inhibit in the nanomolar range and can be distinguished fromother already known CDK-inhibitors such as, e.g., olomoucine androscovitine.

[0005] It has now been found that compounds of general formula I

[0006] in which

[0007] R¹ stands for hydrogen, halogen, C₁-C₆ -alkyl, nitro, or for thegroup —COR⁵, —OCF₃, —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃,

[0008] R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, orC₃-C₁₀-cycloalkyl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl,or C₃-C₁₀-cycloalkyl that is substituted in one or more places in thesame way or differently with hydroxy, halogen, C₁-C₆-alkoxy,C₁-C₆-alkylthio, amino, cyano, C₁-C₆ -alkyl,—NH—(CH₂)_(n)-C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,—SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵,C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or withthe group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl,heteroaryl, —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl itself optionallycan be substituted in one or more places in the same way or differentlywith halogen, hydroxy, C₁-C₆ -alkyl, C₁-C₆-alkoxy, heteroaryl, benzoxyor with the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyland the C₁-C₁₀-alkyl optionally can be interrupted by one or morenitrogen, oxygen and/or sulfur atoms and/or can be interrupted by one ormore ═C═O groups in the ring and/or optionally one or more possibledouble bonds can be contained in the ring, or

[0009] R² stands for the group

[0010] X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or for—OC₃-C₁₀-cycloalkyl, which can be substituted in one or more places inthe same way or differently with a heteroaromatic compound, or

[0011] X and R² together form a C₃-C₁₀-cycloalkyl ring, which optionallycan contain one or more heteroatoms and optionally can be substituted inone or more places with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen,

[0012] A and B, in each case independently of one another, stand forhydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —SR⁷,—S(O)R⁷, —SO₂R⁷, —NHSO₂R⁷, —CH(OH)R⁷, —CR⁷(OH)—R⁷, C₁-C₆-alkylP(O)OR³OR⁴ or —COR⁷, or for

[0013] A and B together form a C₃-C₁₀-cycloalkyl ring that optionallycan be interrupted by one or more nitrogen, oxygen and/or sulfur atomsand/or can be interrupted by one or more ═C═O or ═SO₂ groups in the ringand/or optionally one or more possible double bonds can be contained inthe ring, and the C₃-C₁₀-cycloalkyl ring optionally can be substitutedin one or more places in the same way or differently with hydroxy,halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₃-C₁₀-cycloalkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,—NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂R⁷,C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkoxyOAc, phenyl or with thegroup R⁶, whereby the phenyl itself optionally can be substituted in oneor more places in the same way or differently with halogen, hydroxy,C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃ or —OCF₃,

[0014] R³ and R⁴, in each case independently of one another, stand forhydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy,C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl,dihydroxy-C₁-C₆-alkyl, heteroaryl, heterocyclo-C₃-C₁₀-alkyl,heteroaryl-C₁-C₃-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionallysubstituted with cyano, or for C₁-C₆-alkyl that is optionallysubstituted in one or more places in the same way or differently withphenyl, pyridyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl orC₁-C₆-alkoxy, whereby the phenyl itself can be substituted in one ormore places in the same way or differently with halogen, C₁-C₆-alkyl,C₁-C₆-alkoxy or with the group —SO₂NR³R⁴, or for the group—(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴, or

[0015] R³ and R⁴ together form a C₃-C₁₀-cycloalkyl ring that optionallycan be interrupted by one or more nitrogen, oxygen and/or sulfur atomsand/or can be interrupted by one or more ═C═O groups in the ring and/oroptionally one or more possible double bonds can be contained in thering,

[0016] R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy,

[0017] R⁶ stands for a heteroaryl or C₃-C₁₀-cycloalkyl ring, whereby thering has the above-indicated meaning,

[0018] R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₁₀-cycloalkyl, with theabove-indicated meaning, or for the group —NR³R⁴, or for a C₁-C₁₀-alkyl,C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl or C₃-C₇-cycloalkyl that is substitutedin one or more places in the same way or differently with hydroxy,C₁-C₆-alkoxy, halogen, phenyl, —NR³R⁴ or phenyl, which itself can besubstituted in one or more places in the same way or differently withhalogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl,halo-C₁-C₆-alkoxy, or R⁷ stands for phenyl, which itself can besubstituted in one or more places in the same way or differently withhalogen, hydroxy, C₁-C₆-alkyl or C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, orhalo-C₁-C₆-alkoxy,

[0019] R⁸, R⁹ and

[0020] R¹⁰, in each case independently of one another, stand forhydrogen, hydroxy, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl,C₃-C₁₀-cycloalkyl, aryl, heteroaryl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,C₂-C₁₀-alkinyl or C₃-C₁₀-cycloalkyl that is optionally substituted inone or more places in the same way or differently with hydroxy, halogen,C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl,—NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy -C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,—SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵,C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or withthe group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl,heteroaryl, —(CH₂)_(n)-aryl and —CH₂)_(n)-heteroaryl itself optionallycan be substituted in one or more places in the same way or differentlywith halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃or —OCF₃, and the ring of C₃-C₁₀-cycloalkyl and the C₁-C₁₀-alkyloptionally can be interrupted by one or more nitrogen, oxygen and/orsulfur atoms and/or can be interrupted by one or more ═C═O groups in thering and/or optionally one or more possible double bonds can becontained in the ring, and

[0021] n stands for 0-6,

[0022] as well as isomers, diastereomers, enantiomers and salts thereofthat overcome known drawbacks.

[0023] Alkyl is defined in each case as a straight-chain or branchedalkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl,heptyl, octyl, nonyl and decyl.

[0024] Alkoxy is defined in each case as a straight-chain or branchedalkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy,isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy,pentyloxy, isopentyloxy, or hexyloxy.

[0025] Alkylthio is defined in each case as a straight-chain or branchedalkylthio radical, such as, for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio,tert-butylthio, pentylthio, isopentylthio or hexylthio.

[0026] Cycloalkyl is defined in general as monocyclic alkyl rings, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl or cyclodecyl, but also bicyclic rings ortricyclic rings such as, for example, norbornyl, adamantanyl, etc.

[0027] The ring systems, in which optionally one or more possible doublebonds can be contained in the ring, are defined as, for example,cycloalkenyls, such as cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, or cycloheptenyl, whereby the linkage can be carried outboth to the double bond and to the single bonds.

[0028] If A and B, R³ and R⁴, X and R², in each case independently ofone another, together form a C₃-C₁₀-cycloalkyl ring, which optionallycan be interrupted by one or more heteroatoms, such as nitrogen atoms,oxygen atoms and/or sulfur atoms, and/or can be interrupted by one ormore ═C═O groups in the ring and/or optionally one or more possibledouble bonds can be contained in the ring, however, the above-mentioneddefinitions are also intended to include heteroaryl radical orheterocycloalkyl and heterocycloalkenyl.

[0029] Halogen is defined in each case as fluorine, chlorine, bromine oriodine.

[0030] The alkenyl substituents in each case are straight-chain orbranched, whereby, for example, the following radicals are meant: vinyl,propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl,but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl 1-en-1-yl,but-1-en-3-yl, ethinyl, prop-1-in-1-yl, but-1-in-1-yl, but-2-in-1-yl,but-3-en-1-yl, and allyl.

[0031] Alkinyl is defined in each case as a straight-chain or branchedalkinyl radical that contains 2-6, preferably 2-4 C atoms. For example,the following radicals can be mentioned: acetylene, propin-1-yl,propin-3-yl, but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl,etc.

[0032] The aryl radical in each case comprises 3-12 carbon atoms and ineach case can be benzocondensed.

[0033] For example, there can be mentioned: cyclopropenyl,cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl,azulenyl, biphenyl, fluorenyl, anthracenyl, etc.

[0034] The heteroaryl radical in each case comprises 3-16 ring atoms,and instead of the carbon can contain one or more heteroatoms that arethe same or different, such as oxygen, nitrogen or sulfur, in the ring,and can be monocyclic, bicyclic, or tricyclic and in addition in eachcase can be benzocondensed.

[0035] For example, there can be mentioned:

[0036] Thienyl, faranyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, etc. and benzo derivatives thereof, such as, e.g.,benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl,indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, etc. and benzo derivatives thereof, such as, e.g.,quinolyl, isoquinolyl, etc., or azocinyl, indolizinyl, purinyl, etc. andbenzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,xanthenyl, oxepinyl, etc.

[0037] Heterocycloalkyl stands for an alkyl ring that comprises 3-12carbon atoms, which instead of the carbon contains one or moreheteroatoms that are the same or different, such as, e.g., oxygen,sulfur or nitrogen.

[0038] As heterocycloalkyls, there can be mentioned, e.g.: oxiranyl,oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,quinuclidinyl, etc.

[0039] Heterocycloalkenyl stands for an alkyl ring that comprises 3-12carbon atoms, which instead of the carbon contains one or moreheteroatoms that are the same or different such as, e.g., oxygen, sulfuror nitrogen, and which is partially saturated.

[0040] As heterocycloalkenyls, there can be mentioned, e.g.: pyran,thiin, dihydroacet, etc.

[0041] If an acid group is included, the physiologically compatiblesalts of organic and inorganic bases are suitable as salts, such as, forexample, the readily soluble alkali and alkaline-earth salts, as well asN-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine,1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropane diol, Sovak base, and1-amino-2,3,4-butanetriol.

[0042] If a basic group is included, the physiologically compatiblesalts of organic and inorganic acids are suitable, such as hydrochloricacid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, i.a.

[0043] Those compounds of general formula (I) in which

[0044] R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, nitro, or for thegroup —COR⁵, —OCF₃, —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃,

[0045] R² stands for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, orC₃-C₁₀-cycloalkyl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl,or C₃-C₁₀-cycloalkyl that is substituted in one or more places in thesame way or differently with hydroxy, halogen, C₁-C₆-alkoxy,C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl,—NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,—SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵,C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)-R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or withthe group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl,heteroaryl, —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl itself optionallycan be substituted in one or more places in the same way or differentlywith halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆ alkoxy, heteroaryl, benzoxy orwith the group —CF₃ or —OCF₃, and the ring of the C₃-C₁₀-cycloalkyl andthe C₁-C₁₀-alkyl optionally can be interrupted by one or more nitrogen,oxygen and/or sulfur atoms and/or can be interrupted by one or more ═C═Ogroups in the ring and/or optionally one or more possible double bondscan be contained in the ring, or

[0046] R² stands for the group

[0047] X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or for—OC₃-C₁₀-cycloalkyl, which can be substituted in one or more places inthe same way or differently with a heteroaromatic compound, or

[0048] X and R² together form a C₃-C₁₀-cycloalkyl ring, which optionallycan contain one or more heteroatoms and optionally can be substituted inone or more places with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen,

[0049] A and B, in each case independently of one another, stand forhydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —S—CH₃,—SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂, —S—(CH₂)_(n)CH(OH)CH₂N—R³R⁴,—CH₂P(O)OR³OR⁴, —S—CF₃, —SO—CH₃, —SO₂CF₃, —SO₂—(CH₂) _(n)—N—R³R⁴,—SO₂—NR³R⁴, —SO₂R⁷, —CH—(OH)—CH₃ or for

[0050] A and B together can form a group

[0051] R³ and R⁴, in each case independently of one another, stand forhydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy,C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl,dihydroxy-C₁-C₆-alkyl, heteroaryl, heterocyclo-C₃-C₁₀-alkyl,heteroaryl-C₁-C₃-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl optionallysubstituted with cyano, or for C₁-C₆-alkyl that is optionallysubstituted in one or more places in the same way or differently withphenyl, pyridyl, phenyloxy, C₃-C₆-Cycloalkyl, C₁-C₆-alkyl orC₁-C₆-alkoxy, whereby the phenyl itself can be substituted in one ormore places in the same way or differently with halogen,trifluoromethyl, C₁-C₆-alkyl, C₁-C₆- alkoxy or with the group —SO₂NR³R⁴,or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴ or for

[0052]  which optionally can be substituted with C₁-C₆-alkyl,

[0053] R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy,

[0054] R⁶ stands for the group

[0055] R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, —C₂H₄OH,—NR³R⁴, or the group

[0056] R⁸, R⁹ and

[0057] R¹⁰, in each case independently of one another, stand forhydrogen, hydroxy, C₁-C₆-alkyl, C₃-C₆-cycloalkyl or for the group

[0058]  and

[0059] n stands for 0-6,

[0060] as well as isomers, enantiomers, diastereomers, and saltsthereof, are especially effective.

[0061] Those compounds of general formula I in which

[0062] R¹ stands for hydrogen, halogen, C₁-C₃-alkyl, or for the group—(CH₂)_(n)R⁵,

[0063] R² stands for —CH(CH₃)—(CH₂)_(n)—R⁵, —CH—(CH₂OH)₂, —(CH₂)_(n)R⁷,—CH(C₃H₇)—(CH₂)_(n)—R5, —CH(C₂H₅)—(CH₂)_(n)—R⁵, —CH₂—CN, —CH(CH₃) COCH₃,—CH(CH₃)—C(OH)(CH₃)₂,—CH(CH(OH)CH₃)OCH₃, —CH(C₂H₅)CO—R⁵, C₂-C₄-alkinyl,—(CH₂)_(n)—COR⁵, —(CH₂)_(n)—CO—C₁-C₆-alkyl,—(CH₂)_(n)—C(OH)(CH₃)-phenyl, —CH(CH₃)—C(CH₃)—R⁵,—CH(CH₃)—C(CH₃)(C₂H₅)—R⁵, —CH(OCH₃)—CH₂—R⁵, —CH₂—CH(OH)—R⁵,—CH(OCH₃)—CHR⁵—CH₃, —CH(CH₃)—CH(OH)—CH₂—CH═CH₂,—CH(C₂H₅)—CH(OH)—(CH₂)_(n)—CH₃, —CH(CH₃)—CH(OH)—(CH₂)_(n)—CH₃,—CH(CH₃)—CH(OH)—CH(CH₃)₂, (CH₂OAC)₂, —(CH₂)_(n)—R⁶,—(CH₂)_(n)—(CF₂)_(n)—CF₃, —CH (CH₂)_(n)—R⁵)₂, —CH(CH₃)—CO—NH₂,—CH(CH₂OH)-phenyl, —CH(CH₂OH)—CH(OH)-(CH₂)_(n)R⁵,—CH(CH₂OH)—CH(OH)-phenyl, —CH(CH₂OH)—C₂H₄—R⁵,—(CH₂)_(n)—C≡C(CH₃)═CH—COR⁵, —CH(Ph)—(CH₂)_(n)R⁵, —(CH₂)_(n)—COR⁵,—(CH₂)_(n)PO₃(R⁵)₂, —(CH₂)_(n)—COR⁵, —CH((CH₂)_(n)OR⁵)CO —R⁵,—(CH₂)_(n)CONHCH((CH₂)_(n)R⁵)₂, —(CH₂)_(n)NH—COR⁵,—CH(CH₂)_(n)R⁵—(CH₂)_(n)C₃-C₁₀-cycloalkyl, —(CH₂)_(n)—C₃-C₁₀-cycloalkyl,C₃-C₁₀-cycloalkyl; C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl,—(CH₂)_(n)—O—(CH₂)_(n)—R⁵, —(CH₂)_(n)—NR³R⁴ that is optionallysubstituted in one or more places in the same way or differently withhydroxy, C₁-C₆-alkyl or the group —COONH(CH₂)_(n)CH₃ or —NR³R⁴,—CH(C₃H₇)—(CH₂)_(n)—OC(O)—(CH₂)_(n)—CH₃, —(CH₂)_(n)—R⁵,—C(CH₃)₂—(CH₂)_(n)—R⁵, —C(CH₂)_(n)(CH₃)—(CH₂)_(n)R⁵,—C(CH₂)_(n)—(CH₂)_(n)R⁵, —CH(t-butyl)—(CH₂)_(n)—R⁵,—CCH₃(C₃H₇)—(CH₂)_(n)R⁵, —CH(C₃H₇)—(CH₂)_(n)—R⁵, —CH(C₃H₇)—COR⁵,—CH(C₃H₇)—(CH₂)_(n)—OC(O)—NH—Ph, —CH((CH₂)_(n)(C₃H₇))—(CH₂)_(n)R⁵,—CH(C₃H₇)—(CH₂)_(n)—OC(O)—NH—Ph(OR⁵)₃, —NR³R⁴, —NH—(CH₂)_(n)—NR³R⁴,R⁵—(CH₂)_(n)—C*H—CH(R⁵)—(CH₂)_(n)—R⁵, —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CO—R⁵,—OC(O)NH—C₁-C₆-alkyl or —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CH—((CH₂)_(n)R⁵)₂, orfor C₃-C₁₀-cycloalkyl, which is substituted with the group

[0064]  or for the group

[0065] X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or

[0066] R² stands for the group

[0067]  or

[0068] X and R² together form a group

[0069] A and B, in each case independently of one another, stand forhydrogen, hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —S—CH₃,—SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂, —S(CH₂)_(n)CH(OH)CH₂N—R³R⁴,—CH₂PO(OC₂H₅)₂, —S—CF₃, —SO—CH₃, —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴,—SO₂—NR³R⁴, —SO₂R⁷, —CH(OH)—CH₃, —COOH, —CH((CH₂)_(n)R⁵)₂, —(CH₂)_(n)R⁵,—COO—C₁-C₆-alkyl, —CONR³R⁴ or for

[0070] A and B together can form a group

[0071] R³ and R⁴, in each case independently of one another, stand forhydrogen, phenyl, benzyloxy, C₁-C₂-alkyl, C₁-C₆-alkoxy,C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl,dihydroxy-C₁-C₆-alkyl, heteroaryl, heterocyclo-C₃-C₁₀-alkyl,heteroaryl-C₁-C₃-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionallysubstituted with cyano, or for C₁-C₆-alkyl that is optionallysubstituted in one or more places in the same way or differently withphenyl, pyridyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl orC₁-C₆-alkoxy, whereby the phenyl itself can be substituted in one ormore places in the same way or differently with halogen,trifluoromethyl, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴,or for the group —CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴ or for

[0072]  which optionally can be substituted with C₁-C₆-alkyl,

[0073] R⁵ stands for hydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,benzoxy, C₁-C₆-alkylthio or C₁-C₆-alkoxy,

[0074] R⁶ stands for the group

[0075] R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl,—(CH₂)_(n)OH, —NR³R⁴ or the group

[0076] R⁸, R⁹ and

[0077] R¹⁰ stand for hydrogen, hydroxy, C₁-C₆-alkyl or for the group—(CH₂)_(n)—COOH, and

[0078] n stands for 0-6,

[0079] as well as isomers, diastereomers, enantiomers and salts thereof,have proven quite especially effective.

[0080] The compounds according to the invention essentially inhibitcyclin-dependent kinases, upon which is based their action, for example,against cancer, such as solid tumors and leukemia; auto-immune diseasessuch as psoriasis, alopecia, and multiple sclerosis,chemotherapy-induced alopecia and mucositis; cardiovascular diseasessuch as stenoses, arterioscleroses and restenoses; infectious diseases,such as, e.g., by unicellular parasites, such as trypanosoma, toxoplasmaor plasmodium, or produced by fungi; nephrological diseases, such as,e.g., glomerulonephritis, chronic neurodegenerative diseases, such asHuntington's disease, amyotropic lateral sclerosis, Parkinson's disease,AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases,such as ischemias of the brain and neurotraumas; viral infections, suchas, e.g., cytomegalic infections, herpes, Hepatitis B and C, and HIVdiseases.

[0081] The eukaryotic cell division ensures the duplication of thegenome and its distribution to the daughter cells by passing through acoordinated and regulated sequence of events. The cell cycle is dividedinto four successive phases: the G1 phase represents the time before theDNA replication, in which the cell grows and is sensitive to externalstimuli. In the S phase, the cell replicates its DNA, and in the G2phase, preparations are made for entry into mitosis. In mitosis (Mphase), the replicated DNA separates, and cell division is completed.

[0082] The cyclin-dependent kinases (CDKs), a family of serine/threoninekinases, whose members require the binding of a cyclin (Cyc) as aregulatory subunit in order for them to activate, drive the cell throughthe cell cycle. Different CDK/Cyc pairs are active in the various phasesof the cell cycle. CDK/Cyc pairs that are important to the basicfunction of the cell cycle are, for example, CDK4(6)/CycD, CDK2/CycE,CDK2/CycA, CDK1/CycA and CDK1/CycB. Some members of the CDK enzymefamily have a regulatory function by influencing the activity of theabove-mentioned cell cycle CDKs, while no specific function could beassociated with other members of the CDK enzyme family. One of thelatter, CDK5, is distinguished in that it has an atypical regulatorysubunit (p35) that deviates from the cyclins, and its activity ishighest in the brain.

[0083] The entry into the cell cycle and the passage through the“restriction points,” which marks the independence of a cell fromfurther growth signals for the completion of the cell division that hasbegun, are controlled by the activity of the CDK4(6)/CycD and CDK2/CycEcomplexes. The essential substrate of these CDK complexes is theretinoblastoma protein (Rb), the product of the retinoblastoma tumorsuppressor gene. Rb is a transcriptional co-repressor protein. Inaddition to other, still largely little understood mechanisms, Rb bindsand inactivates transcription factors of the E2F type and formstranscriptional repressor complexes with histone-deacetylases (HDAC)(Zhang, H. S. et al. (2000). Exit from G1 and S Phase of the Cell Cycleis Regulated by Repressor Complexes Containing HDAC₁-Rb-hSWI/SNF andRb-hSWI/SNF. Cell 101, 79-89). By the phosphorylation of Rb by CDKs,bonded E2F transcription factors are released and result intranscriptional activation of genes, whose products are required for theDNA synthesis and the progression through the S-phase. In addition, theRb-phosphorylation brings about the breakdown of the Rb-HDAC complexes,by which additional genes are activated. The phosphorylation of Rb byCDK's is to be treated as equivalent to exceeding the “restrictionpoints.” For the progression through the S-phase and its completion, theactivity of the CDK2/CycE and CDK2/CycA complexes is necessary, e.g.,the activity of the transcription factors of the E2F type is turned offby means of phosphorylation by CDK2/CycA as soon as the cells areentered into the S-phase. After replication of DNA is complete, the CDK1in the complex with CycA or CycB controls the entry into and the passagethrough phases G2 and M (FIG. 1).

[0084] According to the extraordinary importance of the cell-divisioncycle, the passage through the cycle is strictly regulated andcontrolled. The enzymes that are necessary for the progression throughthe cycle must be activated at the correct time and are also turned offagain as soon as the corresponding phase is passed. Correspondingcontrol points (“checkpoints”) stop the progression through the cellcycle if DNA damage is detected, or the DNA replication or the creationof the spindle device is not yet completed.

[0085] The activity of the CDKs is controlled directly by variousmechanisms, such as synthesis and degradation of cyclins, complexing ofthe CDKs with the corresponding cyclins, phosphorylation anddephosphorylation of regulatory threonine and tyrosine radicals, and thebinding of natural inhibitory proteins. While the amount of protein ofthe CDKs in a proliferating cell is relatively constant, the amount ofthe individual cyclins oscillates with the passage through the cycle.Thus, for example, the expression of CycD during the early G1 phase isstimulated by growth factors, and the expression of CycE is inducedafter the “restriction points” are exceeded by the activation of thetranscription factors of the E2F type. The cyclins themselves aredegraded by the ubiquitin-mediated proteolysis. Activating andinactivating phosphorylations regulate the activities of the CDKs, forexample phosphorylate CDK-activating kinases (CAKs) Thr160/161 of theCDK1, while, by contrast, the families of Wee1/Myt1 inactivate kinasesCDK1 by phosphorylation of Thr14 and Tyr15. These inactivatingphosphorylations can be destroyed in turn by cdc25 phosphatases. Theregulation of the activity of the CDK/Cyc complexes by two families ofnatural CDK inhibitor proteins (CKIs), the protein products of the p21gene family (p21, p27, p57) and the p16 gene family (p15, p16, p18, p19)is very significant. Members of the p21 family bind to cyclin complexesof CDKs 1,2,4,6, but inhibit only the complexes that contain CDK1 orCDK2. Members of the p16 family are specific inhibitors of the CDK4- andCDK6 complexes.

[0086] The plane of control point regulation lies above this complexdirect regulation of the activity of the CDKs. Control points allow thecell to track the orderly sequence of the individual phases during thecell cycle. The most important control points lie at the transition fromG1 to S and from G2 to M. The G1 control point ensures that the celldoes not initiate any DNA synthesis unless it has proper nutrition,interacts correctly with other cells or the substrate, and its DNA isintact. The G2/M control point ensures the complete replication of DNAand the creation of the mitotic spindle before the cell enters intomitosis. The G1 control point is activated by the gene product of thep53 tumor suppressor gene. p53 is activated after detection of changesin metabolism or the genomic integrity of the cell and can triggereither a stopping of the cell cycle progression or apoptosis. In thiscase, the transcriptional activation of the expression of the CDKinhibitor protein p21 by p53 plays a decisive role. A second branch ofthe G1 control point comprises the activation of the ATM and Chk1kinases after DNA damage by UV light or ionizing radiation and finallythe phosphorylation and the subsequent proteolytic degradation of thecdc25A phosphatase (Mailand, N. et al. (2000). Rapid Destruction ofHuman cdc25A in Response to DNA Damage. Science 288, 1425-1429). Ashutdown of the cell cycle results from this, since the inhibitoryphosphorylation of the CDKs is not removed. After the G2/M control pointis activated by damage of the DNA, both mechanisms are involved in asimilar way in stopping the progression through the cell cycle.

[0087] The loss of the regulation of the cell cycle and the loss offunction of the control points are characteristics of tumor cells. TheCDK-Rb signal path is affected by mutations in over 90% of human tumorcells. These mutations, which finally result in inactivatingphosphorylation of the RB, include the over-expression of D- andE-cyclins by gene amplification or chromosomal translocations,inactivating mutations or deletions of CDK inhibitors of the p16 type,as well as increased (p27) or reduced (CycD) protein degradation. Thesecond group of genes, which are affected by mutations in tumor cells,codes for components of the control points. Thus p53, which is essentialfor the G1 and G2/M control points, is the most frequently mutated genein human tumors (about 50%). In tumor cells that express p53 withoutmutation, it is often inactivated because of a greatly increased proteindegradation. In a similar way, the genes of other proteins that arenecessary for the function of the control points are affected bymutations, for example ATM (inactivating mutations) or cdc25phosphatases (over-expression).

[0088] Convincing experimental data indicate that CDK2/Cyc complexesoccupy a decisive position during the cell cycle progression: (1) Bothdominant-negative forms of CDK2, such as the transcriptional repressionof the CDK2 expression by anti-sense oligonucleotides, produce astopping of the cell cycle progression. (2) The inactivation of the CycAgene in mice is lethal. (3) The disruption of the function of theCDK2/CycA complex in cells by means of cell-permeable peptides resultedin tumor cell-selective apoptosis (Chen, Y. N. P. et al. (1999).Selective Killing of Transformed Cells by Cyclin/Cyclin-Dependent Kinase2 Antagonists. Proc. Natl. Acad. Sci USA 96, 4325-4329).

[0089] Changes of the cell cycle control play a role not only incarcinoses. The cell cycle is activated by a number of viruses, both bytransforming viruses as well as by non-transforming viruses, to makepossible the replication of viruses in the host cell. The false entryinto the cell cycle of normally post-mitotic cells is associated withvarious neurodegenerative diseases. The mechanisms of the cell cycleregulation, their changes in diseases and a number of approaches todevelop inhibitors of the cell cycle progression and especially the CDKswere already described in a detailed summary in several publications(Sielecki, T. M. et al. (2000). Cyclin-Dependent Kinase Inhibitors:Useful Targets in Cell Cycle Regulation. J. Med. Chem. 43, 1-18; Fry, D.W. & Garrett, M. D. (2000). Inhibitors of Cyclin-Dependent Kinases asTherapeutic Agents for the Treatment of Cancer. Curr. Opin. Oncol. Endo.Metab. Invest. Drugs 2, 40-59; Rosiania, G. R. & Chang, Y. T. (2000).Targeting Hyperproliferative Disorders with Cyclin-Dependent KinaseInhibitors. Exp. Opin. Ther. Patents 10, 215-230; Meijer L. et al.(1999). Properties and Potential Applications of Chemical Inhibitors ofCyclin-Dependent Kinases. Pharmacol. Ther. 82, 279-284; Senderowicz, A.M. & Sausville, E. A. (2000). Preclinical and Clinical Development ofCyclin-Dependent Kinase Modulators. J. Natl. Cancer Inst. 92, 376-387).

[0090] To use the compounds according to the invention as pharmaceuticalagents, the latter are brought into the form of a pharmaceuticalpreparation, which in addition to the active ingredient for enteral orparenteral administration contains suitable pharmaceutical, organic orinorganic inert carrier materials, such as, for example, water, gelatin,gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The pharmaceutical preparations can bepresent in solid form, for example as tablets, coated tablets,suppositories, or capsules, or in liquid form, for example as solutions,suspensions, or emulsions. Moreover, they optionally contain adjuvants,such as preservatives, stabilizers, wetting agents or emulsifiers; saltsfor changing the osmotic pressure or buffers. These pharmaceuticalpreparations are also subjects of this invention.

[0091] For parenteral administration, especially injection solutions orsuspensions, especially aqueous solutions of active compounds inpolyhydroxyethoxylated castor oil, are suitable.

[0092] As carrier systems, surface-active adjuvants such as salts ofbile acids or animal or plant phospholipids, but also mixtures thereof,as well as liposomes or their components can also be used.

[0093] For oral administration, especially tablets, coated tablets orcapsules with talc and/or hydrocarbon vehicles or binders, such as, forexample, lactose, corn or potato starch, are suitable. Theadministration can also be carried out in liquid form, such as, forexample, as a juice, to which optionally a sweetener is added.

[0094] Enteral, parenteral and oral administrations are also subjects ofthis invention.

[0095] The dosage of the active ingredients can vary depending on themethod of administration, age and weight of the patient, type andseverity of the disease to be treated and similar factors. The dailydose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be givenas a single dose to be administered once or divided into two or moredaily doses.

[0096] Subjects of this invention also include the use of compounds ofgeneral formula I for the production of a pharmaceutical agent fortreating cancer, auto-immune diseases, cardiovascular diseases,chemotherapy agent-induced alopecia and mucositis, infectious diseases,nephrological diseases, chronic and acute neurodegenerative diseases andviral infections, whereby cancer is defined as solid tumors andleukemia; auto-immune diseases are defined as psoriasis, alopecia andmultiple sclerosis; cardiovascular diseases are defined as stenoses,arterioscleroses and restenoses; infectious diseases are defined asdiseases that are caused by unicellular parasites; nephrologicaldiseases are defined as glomerulonephritis; chronic neurodegenerativediseases are defined as Huntington's disease, amyotrophic lateralsclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease;acute neurodegenerative diseases are defined as ischemias of the brainand neurotraumas; and viral infections are defined as cytomegalicinfections, herpes, hepatitis B or C, and HIV diseases.

[0097] Subjects of this invention also include pharmaceutical agents fortreating the above-cited diseases, which contain at least one compoundaccording to general formula I, as well as pharmaceutical agents withsuitable formulation substances and vehicles.

[0098] The compounds of general formula I according to the inventionare, i.a., excellent inhibitors of the cyclin-dependent kinases, such asCDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as theglycogen-synthase-kinase (GSK-3β).

[0099] If the production of the starting compounds is not described,these compounds are known or can be produced analogously to knowncompounds or to processes that are described here. It is also possibleto perform all reactions that are described here in parallel reactors orby means of combinatory operating procedures.

[0100] The isomer mixtures can be separated into the enantiomers or E/Zisomers according to commonly used methods, such as, for example,crystallization, chromatography or salt formation.

[0101] The production of the salts is carried out in the usual way by asolution of the compound of formula I being mixed with the equivalentamount of or excess base or acid, which optionally is in solution, andthe precipitate being separated or the solution being worked up in theusual way.

[0102] Production of the Compounds According to the Invention

[0103] The following examples explain the production of the compoundsaccording to the invention, without the scope of the claimed compoundsbeing limited to these examples.

[0104] The compounds of general formula I according to the invention canbe produced according to the following general diagrams of the process:

EXAMPLE 1

[0105] Production of5-Bromo-N2-(4-difluoromethylthiophenyl)-N4-2-propynyl-2,4pyrimidinediamine (carried out according to process diagram 1) (compound 23).

[0106] 245 mg (1 mmol) of ²-chloro-⁴-2-propynylaminopyrimidine isdissolved in 2 ml of acetonitrile, and a suspension of4-(difluoromethylthio)-aniline hydrochloride [produced from 352 mg (2mmol) of 4-(difluoromethylthio)-aniline, 1 ml of acetonitrile and 0.5 mlof aqueous HCl (4M in dioxane)] is added at room temperature. Then, thereaction mixture is refluxed overnight under N₂ atmosphere. Aftercooling, the mixture is filtered, the remaining solid phase is washedwith H₂O and dried. A yield of 328 mg (85%) of the product can beexpected

6H 8.25 (s, 1H) Yield: 2C 7.86 (d, 2H) 85% H 7.51 (d, 2H) 7.38 (t, 56.8Hz, 1H) Melting point: >235° C. 4C 4.18 (m, 2H) H⁺ 3.16 (sb, 1H) 10.24(sb, 1H) NH 8.17 (sb, 1H)

EXAMPLE 2

[0107] Production of5-bromo-N-(3-(oxiranylmethoxy)phenyl)-2-(2-propynyloxy)-2-pyrimidinamine(compound 51) and carried out according to process diagram 2.

[0108] 1.55 g (4.9 mmol) of compound 20 is dissolved in 5.5 ml ofepibromohydrin, and 1.38 g of K₂CO₃ and 65 mg of tetrabutylammoniumbromide are added to it. The reaction mixture is stirred under nitrogenatmosphere at 100° C. for 1 hour. After ethyl acetate is added, theresulting precipitate is collected and recrystallized from ethanol. Theproduct yield is 1.15 g (62%) as a white powder.

6H 8.45 (s, 1H) 2CH 7.47 (s, 1H) 7.32 (d, 1H) Yield: 62% 7.20 (t, 1H)6.40 (d, 1H) Melting point: 173° C. 4.32 (dd, 1H) 3.82 (dd, 1H) 3.3-3.4(m, 1H) 2.87 (t, 1H) 2.72 (dd, 1H) 4CH 5.13 (d, 2H) 3.67 (t, 1H) NH 9.84(sb, 1H)

[0109] Substance 40 is produced analogously to Example 2.

6-H 8.36 (s, 1H) Chromatography: 2CH 7.60 (d, 1H) H/EA 1:3 0.5% TEA 6.91(d, 1H) 4.28 (dd, 1H) 3.79 (dd, 1H) Yield: 38% 3.31 (m, 1H) Meltingpoint: 140-141° C. 2.70 (dd, 1H) 4CH 5.07 (d, 12H) 3.65 (t, 1H) NH 9.65(sb, 1H) OH

EXAMPLE 3

[0110] Production of1-(4-((5-bromo-4-(2-propynyloxy)-pyrimidin-2-yl)-amino)phenoxy)-3-(4-phenylpiperazin-1-yl)-2-propanol(compound 41).

[0111] 0.2 ml of a 0.5 M 4-phenylpiperazine solution in DMPU is added toa solution of 19 mg (0.05 mmol) of substance 51 inN,N′-dimethylpropylurea (DMPU). The reaction mixture is kept for 18hours at a temperature of 80° C. After cooling, 3.5 ml of tertiary butylmethyl ether is added, and the organic phase is extracted 5 times with1.5 ml of H₂0 and then evaporated in a vacuum. The remaining residue ischromatographed on 1.7 g (15 μM) of Lichrosphere Si60 (gradient:dichloromethane/hexane 1:1 to DCM and then dichloromethane/methanol 99:1to 93:7). A product yield of 17 mg (64%) is achieved.

[0112] Similarly produced are also the following compounds: No.Structure No. Structure  96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

[0113] The following compounds were similarly produced in the describedexamples. No. Structure Name 28

5-Bromo-N2-(4-(2-diethylaminoethylsulfonyl)phenyl)-N4-2-propynyl-2,4-pyrimidine diamine 29

1-(4-[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]amino-phenylthio)-3-(diethylamino)-2- propanol 32

5-Bromo-N2-(3-phenylsulfonylphenyl)-N4-2-propynyl- 2,4-pyrimidinediamine 33

N-[4-[[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]amino]-benzenesulfonyl]morpholine 41

1-(4-((5-Bromo-4-(2-propynyloxy)-pyrimidin-2-yl)-amino)phenoxy)-3-(4-phenylpiperazin-1-yl)-2-propanol 57

N-[5-Bromo-4-((2R)-1-hydroxy-4-methyl-2-butylamino)-2-pyrimidinyl]-indazol-5-amine 58

4-[[5-Fluoro-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-pyrimidinyl]amino]-benzenesulfonamide 59

4-[[5-Iodo-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-pyrimidinyl]amino]-benzenesulfonamide 62

4-[[5-Fluoro-4-(2-propynylamino)-2-pyrimidinyl]amino]-benzenesulfonamide 65

4-[[5-Ethyl-4-(2-propynylamino)-2-pyrimidinyl]amino]- benzenesulfonamide66

1-[4-[(5-Iodo-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-pyrimidinyl)amino]phenyl]-ethanone 68

1-[4-[(5-Ethyl-4-((2R)-1-hydroxy-3-methyl-2-butylamino)-2-pyrimidinyl)amino]phenyl]-ethanone 72

4-[[5-Bromo-4-(2-(2-oxo-imidazolin-1-yl)ethylamine)-2-pyrimidinyl]amino]-benzenesulfonamide 73

4-[[5-Bromo-4-(2,2,3,3,3-pentafluoropropyloxy)-2-pyrimidinyl]amino]-benzenesulfonamide 75

4-[[5-Bromo-4-(1,3-bisacetoxy-2-propyloxy)-2-pyrimidinyl]amino]-benzenesulfonamide 76

4-[[5-Bromo-4-(1,3-dihydroxy-2-propyloxy)-2-pyrimidinyl]amino]-benzenesulfonamide 79

N□-(5-Bromo-2-(4-sulfamoylphenyl)amino-pyrimidin-4-yl)- L-alanine amide83

1-[4-[(5-Bromo-4-(2-propynylamino)-2- pyrimidinyl)amino]phenyl]-ethanol

[0114] The following compounds were produced analogously to thedescribed synthesis processes according to Diagram 1 or 2:

[0115] All NMR spectra are measured in the indicated solvent or in DMSO.

Bsp.-Nr. 37 38 39 5 6-H 8.34 (s, 1H) 8.39 (s, 1H) 8.30 (s, 1H) 8.00 (s,1H) 2CH 12.88 9.28 (s, 1H) 7.74 (s, 1H) 7.52 (d, 2H) (sb, 1H) 8.79 (s,1H) 7.44 (d, 1H) 6.65 (d, 2H) 8.07 (s, 1H) 7.70 (d, 1H) 7.22 (d, 1H)7.93 (s, 1H) 8.04 (d, 1H) 3.98 (t, 2H) 7.41 (d, 1H) 3.13 (t, 2H) 7.562.99 (s, 3H) 4CH (dd, 1H) 4.19 (d, 2H) 4.16 (d, 2H) 4.09 (d, 2H) 3.22(sb, 1H) 3.28 (sb, 1H) 3.09 (s, 1H) NH 4.15 10.43 (sb, 1H) 10.6(1 H)9.00 (s, 1H) (dd, 2H) 8.45 (sb, 1H) 8.75 (1H) 8.96 (s, 1H) 3.18 (t, 1H)7.31 (t, 1H) 9.30 (sb, 1H) 7.39 (tb, 1H) Chro- EA + 0.5% —Kristallisiert — mato- TEA MeOH graphie 10% 36% 73% 20% Aus- beuteSchmp. 231° C. >235° C. 237° C. 157° C.

Beispiel 16 24 36 35 Nr. 6-H 8.80 (s, 1H) 8.30 (s, 1H) 8.18 (s, 1H) 8.14(s, 1H) 2CH 7.67 (d, 2H) 7.94 (d, 2H) 7.67 (s, 1H) 8.28 (s, 1H) 7.27 (d,2H) 7.63 (d, 2H) 7.54 (d, 1H) 7.98 (d, 1H) 2.47 (s, 3H) 7.24 (t, 1H)7.41 (t, 1H) 6.92 (d, 1H) 7.25 (d, 1H) 4CH 4.17 (dd, 2H) 4.17 (dd, 2H)4.20 (dd, 2H) 4.14 (dd, 2H) 3.75 (t, 1H) 3.18 (t, 1H) 3.12 (sb, 1H) 3.04(sb, 1H) NH 10.55 10.45 9.78 (sb, 1H) 9.58 (sb, 1H) (sb, 1H) (sb, 1H)7.95 (sb, 1H) 7.46 (sb, 1H) 8.68 (sb, 1H) 8.22 (sb, 1H) Chrom. — — — —Aus- 94% 86% 73% 69% beute Schmp. 232-234° C. 160° C. 194° C. 143° C.

Beispiel 27 36 34 21 Nr. 6-H 8.18 (s, 1H) 8.26 (s, 1H) 8.25 (s, 1H) 8.17(s, 1H) 2CH 8.73 (s, 1H) 8.12 (s, 1H) 8.16 (s, 1H) 8.74 (s, 1H) 7.62 (d,1H) 7.35- 7.43 (d, 1H) 7.43 (d, 1H) 7.72 (t, 1H) 7.55 (m, 3H) 7.52 (t,1H) 7.52 (t, 1H) 8.31 (d, 1H) 8.06 (d, 1H) 8.01 (d, 1H) 8.08 (d, 1H)2.78 (m, 2H) 3.43 (t, 2H) 1.35 (mc, 2H) 3.70 (t, 2H) 1.24 (mc, 2H) 0.80(t, 3H) 4CH 4.18 (dd, 2H) 4.21 (d, 2H) 3.06 (t, 1H) 3.09 (sb, 1H) 3.08(t, 1H) NH 10.02 (s, 1H) 10.3 (sb, 1H) 9.79 (s, 1H) 7.49 (sb, 1H) 9.68(sb, 1H) 8.13 (sb, 1H) 7.55 (tb, 1H) OH 7.30 (sb, 2H) 4.90 (sb, 1H)Chrom. — krist.EtOH — — Aus- 69% 64% 87% 59% beute Schmp. 144° C. 219°C. 220° C. 192.5- 193.5° C.

Beispiel 31 25 23 11 Nr. 6-H 8.25 (s, 1H) 8.14 (s, 1H) 8.25 (s, 1H) 8.29(s, 1H) 2CH 7.65 (d, 2H) 8.01 (d, 2H) 7.86 (d, 2H) 7.95 (d, 2H) 7.24 (d,2H) 7.56 (d, 2H) 7.51 (d, 2H) 7.78 (d, 2H) 3.19 2.70 (s, 3H) 7.38 (d,21.3 Hz, 2 (t, 56.8 Hz, 1H) H) 3.95 4CH (mc, 4H) 4.15 (dd, 2H) 4.18 (m,2H) 4.19 (d, 2H) 1.20 (t, 6H) 3.14 (t, 1H) 3.16 (sb, 1H) 3.18 (sb, 1H)NH 9.69 (sb, 1H) 10.24 (sb, 1H) 10.40 4.17 (sb, 2H) 7.55 (tb, 1H) 8.17(sb, 1H) (sb, 1H) 3.15 (sb, 1H) 8.24 (sb, 1H) 10.19 7.15 (sb, 2H) (sb,1H) 8.34 (sb, 1H) Chrom. EA kris. DCM/MeOH — krist. Aus- H/DIPE 95:5 85%DIPE/EtOH beute 23% 25% 17 Schmp. 198° C. 217-218° C. >235° C. >235° C.

Beispiel 44 45 4 Nr. 6-H 8.34 (s, 1H) 8.34 (s, 1H) 8.23 n(sb, 1H) 2CH7.93 (d, 2H) 7.74 (mc, 4H) 7.39 (d, 2H) 7.79 (d, 2H) 6.79 (d, 2H) 4CH4.20 (sb, 2H) 4.55 (q, 1H) 3.52-3.71 (2H) 3.31 (sb, 1H) 1.98 (dq, 2H)3.97 (mc, 1H) 0.94 (t, 3H) 1.96 (mc, 1H) 3.61 (s, 3H) 0.91 (d, 3H) NH11.03 (sb, 1H) 10.60 (s, 1H) 0.85 (d, 3H) 9.04 (sb, 1H) 7.97 (d, 1H)10.35 (sb, 1H) 7.34 (sb, 2H) 7.31 (db, 2H) 7.76 (sb, 1H) Chrom. krist.EtOH krist. EtOH — Aus- 27% 48% 52% beute Schmp. 252° C. 235° C.252-253° C.

Beispiel 10 15 3 19 Nr. 6-H 8.27 (s, 1H) 8.17 (s, 1H) 7.97 (s, 1H)8.20-8.35 2H 7.80 7.60 (d, 2H) 7.44 (d, 2H) (2H) (mc, 4H) 7.24 (d, 2H)6.67 (d, 2H) 7.90 (sb, 1H) 2.44 (s, 3H) 7.50-7.64 (2H) 3.46 (t, 2H) 4H3.5-3.7 (2H) 3.50-3.65 3.70 (t, 2H) 3.66 40.1 (mc, 1H) (4H) (mc, 2H)1.98 (mc, 1H) 4.12 (mc, 1H) 3-56-3.66 n. obs. 0.94 (d, 3H) (4H) 2.040.90 (d, 3H) 4.28 (mc, 1H) NH (mc, 1H) 9.95 (sb, 1H) OH 0.97 (d, 3H)6.96 (sb, 1H) 8.98 (sb, 1H) 0.94 (d, 3H) ca.4, sehr 5.97 (db, 1H) 10.40breit 8.90 (sb, 1H) NH and OH (sb, 1H) 4.80 (tb, 2H) sind sehr 7.18 (sb,2H) breit n. obs. Chrom. — — — Kristallisiert Wasser Aus- 43% 27% 76%52% beute Schmp. 252-253° C. 192-193° C. 257‥258° C. 209-210° C.

Beispiel 9 14 55 50 Nr. 6-H 8.30 (s, 1H) 8.30 (s, 1H) 8.11 (s, 1H) 8.17(s, 1H) 2H 7.82 7.55 (d, 2H) 7.87 (s, 4H) 7.95 (d, 2H) (mc, 4H) 7.30 (d,2H) 2.50 (s) 7.86 (d, 2H) 2.48 (s, 3H) 2.50 (s) 4H 3.54-3.68 4.19 (mc,1H) 4.17 (dd, 2H) 3.63 (4H) 3.61 (mc, 4H) 3.13 (t, 1H) (mc, 4H) 4.24(mc, 1H) NH 4.24 9.73 (s, 1H) 9.81 (s, 1H) OH (mc, 1H) 10.63 (sb, 1H)6.20 (s, 1H) 7.58 (t, 1H) 7.60 (sb, 1H) 4.88 (t, 2H) 10.59 (b, 1H) 4.4(b) 7.2 (sb) 6.1 (sb) Chrom. Kristallisiert Kristallisiert — Aus- MeOHMeOH/DIPE beute 24% 91 27% 56% Schmp. 247-247° C. 233-234° C. 228-229°C. 241° C.

Beispiel 46 13 52 53 Nr. 6-H 8.07s, 1H) 8.00 (s, 1H) 8.09 (s, 1H) 8.11(s, 1H) 2H 7.91 (d, 2H) 7.68 (d, 2H) 7.88 (s, 4H) 7.86 (s, 4H) 7.69 (d,2H) 7.18 (d, 2H) not abs. 2.44 (s, 3H) 4H 3.30 (t, 2H) 3.54 (q, 2h9 3.32(t, 2H) 3.62 (mc, 2H) n.obs. (mc, 1 2.53 (t, 2H) 1.20 (mc, 1H) 4.06 (mc,1H) H) 2.40-2.45 0.44 (mc, 2H) 2.02 (mc, 1H) 0.45 (4H) 0.30 (mc, 2H)0.97 (d, 3H) (mc, 2H) 3.58 (t, 4H) 0.92 (d, 3H) NH 0.30 9.70 (s, 1H)9.70 (s, 1H) OH (mc, 2H) 9.20 (sb, 1H) 7.21 (t, 1H) 6.24 (d, 1H) 6.81(tb, 1H) 4.80 (sb, 1H) 9.94 (s, 1H) 7.21 (t, 1H) 7.18 (s, 2H) Chrom.H/EA 1:2 — — H/EA 1:2 Aus- 20% 28% 53% 9% beute Schmp. 256° C. 185-186°C. 183° C. 170° C.

Beispiel 1 54 12 60 Nr. 6-H 7.96 (s, 1H) 8.22 (s, 1H) 8.03 (s, 1H) 8.10(s, 1H) 2H 7.43 (d, 2H) 7.93 (d, 2H) 7.68 (d, 2H) 7.92 (d, 2H) 6.67 (d,2H) 7.85 (d, 2H) 7.19 (d, 2H) 7.66 (d, 2H) 2.43 (s, 3H) not. obs. 2.74(t, 2H) 4H 1.20 (d, 3H) 4.26 (d, 2H) 1.20 (d, 3H) 3.61 (mc, 2H) 4.383.12 (sb, 1H) 4.42 (mc, 1H) 4.04 (mc, 1H) (mc, 1H) 3.37 (dd, 1H) 2.01(mc, 1H) 3.37 (dd, 1H) 3.50 (dd, 1H) 0.94 (d, 3H) 3.48 (dd, 1H) 3.34 (s,3H) 0.91 (d, 3H) NH 3.28 (s, 3H) 9.78 (s, 1H) 9.26 (s, 1H) 9.72 (s, 1H)8.92 (sb, 1H) 7.65 (s, 1H) 8.81 (sb, 1H) 6.27 (d, 1H) OH 7.21 (t, 1H)6.42 (d, 1H) 4.80 (sb, 1H) 6.20 (tb, 1H) 4.70 (sb, 1H) Chrom.Kristallisiert Kristalfisiert Kristallisiert. Aus- EA DIPE/MeOH EA beute64% 52% 36% 165.5- 210° C. 91° C. 150-151° C. Schmp. 166° C.

Beispiel 7 17 2 18 8 (D₂O) Nr. 6-H 8.32 (s, 1H) 8.08 (s, 1H) 7.95 (s,1H) 8.32 (s, 1H) 8.14 (s, 1H) 4CH 1.22 (d, 3H) 1.21 (d, 3H) 3.50 (q, 2H)3.10 (m, 2H) 3.06 (sb, 2H) 4.46 4.53 (mc, 1H) 2.50 (t, 2H) 3.52 (m, 4H)3.39 (t, 4H) (mc, 1H) 3.41 (dd, 1H) 2.40 (t, 4H) 3.77-3.97 3.71 (sb, 2H)3.40 (dd, 1H) 3.51 (dd, 1H) 3.59 (t, 4H) (6H) 3.85 (sb, 2H) 3.57 (dd,1H) 3.27 (s, 3H) 3.94 (t, 2H) 2CH 3.28 (s, 3H) 8.53 (s, 1H) 7.45 (d, 2H)8.00 (d, 2H) 7.80 (s, 4H) 7.40 (d, 1H) 6.66 (d, 2H) 8.40 (s, 1H) 7.72(d, 2H 7.50 (t, 1H) 7.55-7.70 7.86 (d, 1H) (2H) 3.40 (t, 2H) 7.85 (d,1H) 3.68 (t, 2H) 3.48 (m, 2H) NH 9.65 (sb, 1H) 8.94 (sb, 1H) 3.70 (m,2H) 10.79 6.47 (db, 1H) 8.79 (sb, 1H) OH (sb, 1H) 4.84 (tb, 1H) 6.70(tb, 1H) 11.16 (sb, 1H) 7.84 (db, 1H) 10.60 (sb, 1H) 7.31 (sb, 2H) 8.20(sb, 1H) Chrom. — — kristall. krist. Wasser Aus- 25% 10% 62% MeOH 25%beute 50% Schmp. 247° Zers. 201-202° C. 227.5- 245° C. Zers. 228.5°C. >275° C.

Beispiel 47 6 22 84 Nr. 5-H 8.74 (s, 1H) 8.31 (s, 1H) 8.31 (s, 1H) 8.47(s, 1H) 2CH 7.87 (d, 2H) 7.47 (d, 2H) 7.76 (d, 2H) 4.48 (t, 2H) 7.74 (d,2H) 6.71 (d, 2H) 7.72 (d, 2H) 2.01 (mc, 2H) 2.58 (s, 3H) 2.44 (mc, 2H)4CH 4.50 (t, 2H) 5.04 (d, 2H) 5.05 (d, 2H) 2.03 (mc, 2H) 3.59 (t, 1H)2.57 (t, 1H) 7.91 (d, 2H) 2.44 (mc, 2H) 2NH 10.14 (s, 1H) 9.02 (sb, 1H)7.47 (sb, 1H) 7.85 (d, 2H) 7.21 (s, 2H) 9.40 (sb, 1H) 2.50 (s) 10.19 (s,1H) Chrom. MeOH/DCM — — Aus- 1:9 66% 8% 11% beute 4% Schmp. 186-187° C.146° C. 165-166° C. 152° C.

Beispiel 86 77 Nr. 5-H 8.47 (s, 1H) 8.48 (s, 1H) 2CH 4.07 (mc, 2H) 5.52(m, 1H) 3.81 (mc, 2H) 3.68 (d, 4H) 3.60 (mc, 2H) 3.48 (mc, 4H) 4CH 3.48(mc, 2H) 1.09 (t, 6H) 3.41 (t, 2H) 7.84 (d, 2H) 1.07 (t, 3H) 2NH 7.84(d, 2H) 7.74 (d, 2H) 7.91 (d, 2H) 8.05 (vb) 10.18 (s2, H) 3.40 (vb)Chrom. — — Aus- 2% 74% beute Schmp. 85° C. 132° C.

Beispiel 40 20 Nr. 6-H 8.36 (s, 1H) 8.40 (s, 1H) 2CH 7.60 (d, 1H) 7.23(s, 1H) 6.91 (d, 1H) 6.42 (d, 1H) 4.28 (dd, 1H) 7.06 (t, 1H) 3.79 (dc,1H) 7.18 (d, 1H) 3.31 (m, 1H) 2.84 (dd, 1H) 2.70 (dd, 1H) 4CH 5.07 (d,12H) 5.12 (d, 2H) 3.65 (t, 1H) 3.60 (sb, 1H) NH 9.65 (sb, 1H) 9.60 (sb,1H) OH 9.21 (sb, 1H) Chrom. H/EA 1:3 krist. DIPE Aus- 0.5% TEA 35% beute38% Schmp. 140-141° C. 174° C.

Beispiel 49 48 29 42 Nr. 6-H 8.14 (s, 1H) 8.10 (s, 1H) 8.09 (s, 1H) 7.87(d, 3.4, 1H) 2H 7.88 (d, 2H) 7.92 (d, 2H) 8.50 (s, 1H) 7.51 (d, 2H) 7.69(d, 2H) 7.66 (d, 2H) 7.86 (d, 1H) 6.66 (d, 2H) not. obs. 7.50 (t, 1H)2.74 (t, 2H) 7.40 (d, 1H) 4H 3.41 (q, 2H) 3.61 (mc, 2H) 3.40 (t, 2H)4.13 (dd, 2H) 2.20 (t, 2H) 4.04 (mc, 1H) 3.52-3.73 3.08 (t, 1H) 1.81 (q,2H) 2.01 (mc, 1H) (4H) 0.94 (d, 3H) 4.09 (mc, 1H) 0.91 (d, 3H) 1.98(mcAH) 0.97 (d, 3H) NH 9.64 (s, 1H) 9.72 (s, 1H) 0.89 (d, 3H) 8.76 (s,1H) 7.64 (t, 1H) 7.65 (s, 1H) 9.68 (s, 1H) 7.74 (tb, 1H) OH 3.5 (vb 6.27(d, 1H) 6.17 (d, 1H) 8.88 (s, 1H) 4.80 (sb, 1H) 4.74 (t, 1H) 4.70 (sb,1H) 4.93 (t, 1H) Chrom. — Krist.MeOH/DI DCM/EA 2:1 H/EA 1:2 Aus- 9% PE26% 29% beute 16% Schmp. 262° C. 150-151° C. 163° C.

Beispiel 43 55 89 88 Nr. 6-H 7.93 (s, 1H) 8.11 (s, 1H) 8.36 (s, 1H) 8.29(s,.1H) 2H 7.52 (d, 2H) 7.87 (s, 4H) 7.7-7.8 (5H) 7.73 (d, 2H) 6.68 (d,2H) 2.50 (s) 7.57 (d, 2H) 4H 3.09 (s, 1H) 4.19 (mc, 1H) 3.66 (mc, 2H)3.7-3.9 (2H) 4.14 (d, 2H) 3.61 (mc, 4H) 4.04 (m, 1H) 5.19 (m, 1H) 1.99(mc, 1H) 7.2-7.4 (5H) 0.94 (d, 3H) 0.89 (d, 3H) NH 8.98 (sb, 2H) 9.73(s, 1H) 11.11 (sb, 1H) 10.50 (s, 1H) 7.50 (s, 1H) 6.20 (s, 1H) 5.029(vb) OH 4.88 (t, 2H) 7.34 (sb, 2H) n. obs. Chrom. H/EA 1:2 krist. MeOH/— — Aus- 35% DIPE 74% 27% beute 27% Schmp. 168° C. 228° C. 248° C. Zers.159° C. Zers.

Beispiel 87 92 91 96 Nr. 6-H 8.09 (s, 1H) 8.10 (s, 1H) 8.09 (s, 1H) 8.06(s, 1H) 2H 7.90 (d, 2H) 7.91 (d, 2H) 7.98 (d, 2H) 7.88 (d, 2H) 7.82 (d,2H) 7.63 (d, 2H) 7.61 (d, 2H) 7.69 (d, 2H) not. obs 2.39 (d, 3H) 2.54(s, 6H) 4H 3.69 (td, 2H) 1.21 (d, 3H) 1.20 (d, 3H) 3.41 (m, 2H) 2.84 (t,2H) 4.45 (mc, 1H) 4.46 (mc, 1H) 1.62 (m, 4H) 7.60 (s, 1H) 3.38 (dd, 1H)3.47 (dd, 1H) 2.41 (m, 2H) 6.86 (s, 1H) 3.51 (dd, 1H) 3.51 (dd, 1H) 5.07(s, 2H) 3.38 (s, 3H) NH 7.34 (tb, 1H) 9.73 (sb, 1H) 9.81 (sb, 1H) 7.32(s, 5H) 9.72 (s, 1H) 7.20 (q, 1H) 6.58 (db, 1H) 9.64 (s, 1H) 7.16 (sb,2H) OH 11.91 (sb, 1H) 6.57 (d, 1H) Chrom. — H bis H/EA 1:1 H bis H/EA —Aus- 16% 21 21% 33% beute 7% Schmp. 210° C. 167-168° C. 105° C. 202° C.

Beispiel 97 98 90 85 Nr. 6-H 8.07 (s, 1H) 8.10 (s, 1H) 8.30 (s, 1H) 2H7.87 (s, 4H) 7.86 (mc, 4H) 7.95 (d, 2H) 2.50 (s, 3H) n. obs. 7.69 (d,2H) 2.48 (s, 3H) 4H 3.41 (m, 2H) 3.68 (t, 2H) 3.50 (q, 2H) 1.61 (m, 4H)2.68 (t, 2H) 1.87 (m, 2H) 2.41 (m, 2H) 4.08 (q, 2H) 2.38 (t, 2H) 5.07(s, 2H) 1.17 (t, §H) 4.03 (q, 2H) 1.13 (t, 3H) NH 7.32 (s, 5H) 9.74 (s,1H) 10.86 (s, 1H) 9.70 (s, 1H) 7.18 (t, 1H) 8.28 (sb, 2H) 7.19 (t, 1H)Chrom. — — — Aus- 23% 32% 53% beute Schmp. 152° C. 172 184° C.

Beispiel 63 94 93 80 Nr. 9.73 (s, 1H) 10.91 (s, 1H) 10.80 (s, 1H) 10.88(s, 1H) 8.25 (s, 1H) 8.34 (s, 1H) 8.30 (s, 1H) 8.40 (s, 1H) 7.95 (d, 2H)7.80 (s, 4H) 7.81 (d, 2H) 8.29 (m, 1H) 7.67 (d, 2H) 7.30 (s, 2H) 7.65(d, 2H) 7.79 (s, 4H) 7.21 (s, 3H) 4.35 (m, 1H) 7.30 (m, 8H) 7.31 (s, 2H)4.12 (s, 2H) 3.58 (m, 2H) 4.95 (d, 1H) 4.75 (dd, 1H) 3.12 (s, 1H) 2.47(m, 2H) 4.38 (m, 1H) 3.65 (m, 1H) 2.03 (s, 3H) 3.59 (d, 1H) 3.49 (m, 1H)1.91 (m, 2H) 2.10 (m, 2H) Aus- 61% 24% 70% 51% beute Schmp. 220 168 243Masse 428 (EI) 462 (ES) 494 (ES) 427 (EI)

Beispiel 120 121 122 123 Nr. 9.65 (s, 1H) 9.68 (s, 1H) 11.30 (s, 1H)10.79 (s, 1H) 8.12 (s, 1H) 8.11 (s, 1H) 8.11 (d, 1H) 8.35 (s, 1H) 7.89(d, 2H) 7.93 (t, 1H) 7.85 (d, 2H) 8.25 (s, 1H) 7.65 (d, 2H) 7.90 (d, 2H)7.72 (d, 2H) 7.80 (s, 4H) 7.15 (s, 2H) 7.65 (d, 2H) 7.31 (s, 2H) 7.30(s, 2H) 6.06 (d, 1H) 7.15 (s, 2H) 6.71 (d, 1H) 3.41 (m, 2H) 4.71 (t, 1H)7.07 (t, 1H) 3.85 (m, 8H) 2.22 (t, 2H) 4.18 (m, 1H) 3.65 (m, 2H) 1.60(m, 4H) 3.67 (t, 1H) 3.56 (s, 3H) 1.30 (m, 2H) 0.95 (s, 9H) 3.07 (q, 2H)2.45 (t, 2H) 2.30 (t, 2H) 1.65 (p, 2H) Aus- 49% 24% 80% 73% beute Schmp.252 Masse 445 (EI) 516 (EI) 334 (EI) 459 (EI)

Beispiel 95 124 Nr. 11.19 (s, 1H) 9.62 (s, 1H) 8.37 (s, 1H) 8.04 (s, 1H)8.11 (d, 1H) 7.88 (m, 3H) 7.80 (s, 4H) 7.66 (d, 2H) 7.31 (s, 2H) 7.13(s, 3H) 3.91 (m, 1H) 3.58 (s, 3H) 1.89 (m, 4H) 3.40 (m, 2H) 1.67 (m, 1H)3.05 (m, 2H) 1.55 (m, 2H) 2.25 (m, 2H) 1.34 (m, 2H) 2.05 (m, 2H) 1.15(m, 1H) 1.32 (m, 3H) Aus- 29% 25% beute Schmp. 255 Masse 425 (EI) 557(ES)

Beispiel 125 126 Nr. 9.62 (s, 1H) 10.91 (s, 1H) 8.04 (s, 1H) 8.38 (s,1H) 7.86 (d, 2H) 7.83 (d, 2H) 7.66 (d, 2H) 7.77 (d, 2H) 7.12 (s, 3H)7.28 (s, 2H) 3.58 (s, 3H) 7.04 (d, 1H) 3.40 (m, 2H) 6.40 (br, 3H) 2.30(t, 2H) 4.35 (m, 1H) 1.60 (m, 4H) 3.87 (m, 1H) 1.32 (m, 2H) 3.60 (d, 2H)1.60 (m, 5H) 3.41 (dd, 1H) 3.28 (dd, 1H) Aus- 27% 46% beute Schmp. 218Masse 471 (EI) 449 (EI)

Beispiel 127 128 129 130 Nr. 9.96 (s, 1H) 9.60 (s, 1H) 9.67 (s, 1H) 9.65(s, 1H) 8.12 (s, 1H) 8.05 (s, 1H) 8.07 (s, 1H) 8.08 (s, 1H) 7.85 (d, 2H)7.90 (d, 2H) 7.87 (d, 2H) 7.87 (d, 2H) 7.69 (d, 2H) 7.69 (d, 2H) 7.75(d, 2H) 7.64 (d, 2H) 7.20 (s, 2H) 7.42 (d, 1H) 7.13 (s, 2H) 7.14 (s, 2H)6.78 (d, 1H) 7.16 (m, 3H) 6.40 (d, 1H) 6.53 (d, 1H) 4.35 (m, 1H) 4.57(t, 2H) 4.91 (br, 1H) 4.62 (d, 1H) 3.48 (m, 2H) 3.70 (m, 1H) 4.23 (m,1H) 3.90 (br, 1H) 1.65 (m, 7H) 3.4 (m, 5H) 3.52 (m, 2H) 3.40 (br, 1H)1.10 (m, 6H) 2.10 (t, 2H) 1.21 (d, 3H) 1.88 (m, 4H) 1.55 (m, 4H) 1.50(m, 2H) 1.30 (m, 2H) 1.30 (m, 2H) Aus- 18% 94% 61% 58% beute Schmp. 220259 262 Masse 485 (EI) 531 (ES) 403 (EI) 443 (EI)

Beispiel 131 132 133 134 Nr. 9.62 (s, 1H) 9.70 (s, 1H) 9.69 (s, 1H)10.85 (s, 1H) 8.08 (s, 1H) 8.11 (s, 1H) 8.11 (s, 1H) 8.31 (s, 1H) 7.92(d, 2H) 7.90 (d, 2H) 7.88 (d, 2H) 7.90 (d, 1H) 7.67 (d, 2H) 7.60 (d, 2H)7.66 (d, 2H) 7.85 (d, 2H) 7.23 (s, 2H) 7.21 (q, 1H) 7.15 (s, 2H) 7.75(d, 2H) 6.75 (t, 1H) 5.25 (d, 1H) 6.52 (d, 1H) 7.54 (s, 1H) 3.22 (d, 2H)4.77 (t, 1H) 4.35 (dd, 1H) 3.90 (m, 1H) 1.95 (s, 3H) 4.02 (m, 1H) 2.29(m, 1H) 3.38 (t, 2H) 1.60 (m, 12H) 3.60 (m, 2H) 1.07 (d, 3H) 2.78 (br,2H) 2.39 (d, 3H) 0.91 (d, 3H) 1.50 (m, 11H) 2.02 (m, 1H) 0.95 (dd, 6H)Aus- 9% 42% 25% 64% beute Schmp. 229 141 Masse 491 (EI) 443 (EI) 444(FAB)

Beispiel 135 136 137 138 Nr. 10.01 (s, 1H) 9.70 (s, 1H) 9.65 (s, 1H)9.70 (s, 1H) 8.28 (s, 1H) 8.11 (s, 1H) 9.58 (s, 1H) 8.10 (s, 1H) 7.81(d, 2H) 7.90 (d, 2H) 8.10 (s, 1H) 7.89 (d, 2H) 7.71 (t, 1H) 7.64 (d, 2H)7.85 (d, 2H) 7.63 (d, 2H) 7.63 (d, 2H) 7.35 (t, 1H) 7.68 (d, 2H) 7.39(t, 1H) 7.45 (br, 1H) 6.55 (d, 1H) 7.40 (m, 2H) 6.68 (d, 1H) 4.34 (dt,2H) 4.65 (t, 1H) 7.18 (m, 4H) 4.34 (dd, 1H) 3.32 (t, 2H) 4.45 (m, 1H)6.94 (t, 1H) 3.36 (m, 3H) 2.71 (br, 2H) 3.53 (m, 1H) 6.75 (d, 1H) 2.25(q, 2H) 3.44 (m, 6H) 4.40 (m, 3H) 2.29 (m, 1H) 2.75 (q, 2H) 2.05 (m, 1H)1.05 (dd, 6H) 1.20 (d, 3H) 0.96 (dd, 6H) Aus- 34% 53% 59% 57% beuteSchmp. Masse 570 (ES) 460 (ES) 549 (ES) 488 (ES)

Beispiel 139 140 141 142 Nr. 9.82 (s, 1H) 9.82 (s, 1H) 9.58 (s, 1H) 9.62(s, 1H) 8.15 (s, 1H) 8.08 (s, 1H) 8.12 (s, 1H) 8.07 (s, 1H) 7.82 (d, 2H)7.96 (d, 2H) 7.83 (d, 2H) 7.87 (d, 2H) 7.64 (d, 2H) 7.75 (t, 1H) 7.68(d, 2H) 7.67 (d, 2H) 7.39 (t, 1H) 7.62 (d, 2H) 7.15 (s, 2H) 7.14 (s, 2H)6.55 (d, 1H) 7.30 (t, 1H) 5.92 (s, 1H) 6.36 (d, 1H) 4.64 (t, 1H) 4.64(t, 1H) 5.28 (t, 1H) 4.81 (t, 1H) 4.50 (t, 1H) 4.14 (m, 2H) 3.50 (d, 2H)4.32 (m, 1H) 3.65 (s, 3H) 3.35 (m, 2H) 1.42 (s, 6H) 3.47 (m, 2H) 3.4 (m,2H) 3.16 (m, 1H) 1.52 (m, 3H) 2.75 (m, 2H) 2.75 (q, 2H) 0.90 (d, 3H)2.35 (m, 1H) 0.86 (d, 3H) 1.00 (dd, 6H) Aus- 20% 63% 23% 8% beute Schmp.Masse 502 (ES) 382 (ES) 415 (EI) 443 (EI)

Beispiel 143 144 145 78 Nr. 10.6 (s, 1H) 10.11 (s, 1H) 11.05 (s, 1H)9.69 (s, 1H) 8.28 (s, 1H) 8.45 (s, 1H) 8.32 (s, 1H) 8.06 (s, 1H) 8.30(m, 5H) 7.86 (d, 2H) 8.08 (d, 1H) 7.88 (d, 2H) 7.48 (d, 1H) 7.78 (d, 2H)7.80 (m, 4H) 7.63 (d, 2H) 7.20 (s, 1H) 7.15 (br, 2H) 7.30 (br, 2H) 7.18(s, 2H) 4.05 (br, 1H) 5.32 (m, 1H) 3.88 (m, 1H) 7.10 (t, 1H) 3.60 (br,2H) 3.91 (m, 2H) 3.65 (m, 1H) 6.65 (d, 1H) 2.01 (m, 1H) 3.53 (m, 2H)1.95 (m, 2H) 4.47 (m, 1H) 0.90 (m, 6H) 2.05 (m, 2H) 1.69 (m, 2H) 3.97(m, 1H) 1.70 (m, 2H) 1.35 (m, 4H) 2.98 (m, 2H) 2.00 (m, 4H) 1.40 (m, 8H)0.85 (t, 3H) Aus- 13% 47% 42% 20% beute Schmp. Masse 392 (EI) 428 (EI)441 (EI) 541 (ES)

Beispiel 146 147 148 149 Nr. 11.13 (s, 1H) 11.18 (s, 1H) 11.15 (s, 1H)9.19 (s, 1H) 8.38 (s, 1H) 8.35 (s, 1H) 8.35 (s, 1H) 8.30 (s, 1H) 7.92(d, 2H) 7.90 (s, 4H) 7.90 (d, 2H) 8.02 (s, 1H) 7.75 (m, 3H) 7.62 (d, 1H)7.65 (m, 3H) 7.62 (m, 1H) 4.04 (m, 1H) 4.02 (m, 1H) 4.01 (m, 1H) 6.85(d, 1H) 3.80 (s, 3H) 3.62 (m, 2H) 3.60 (m, 6H) 6.05 (d, 1H) 3.65 (m, 2H)3.02 (s, 3H) 2.85 (m, 4H) 4.03 (m, 1H) 2.00 (m, 1H) 2.00 (m, 1H) 2.00(m, 1H) 3.56 (m, 2H) 0.96 (d, 3H) 0.95 (d, 3H) 0.95 (d, 3H) 1.96 (m, 1H)0.89 (d, 3H) 0.89 (d, 3H) 0.85 (d, 3H) 0.97 (d, 3H) 0.90 (d, 3H) Aus-86% 33% 79% 42% beute Schmp. 225 211 232 241 Masse 408 (EI) 428 (EI) 501(EI) 411 (ES)

Beispiel 150 151 152 153 Nr. 11.19 (s, 1H) 10.96 (s, 1H) 9.50 (s, 1H)12.90 (s, 1H) 10.80 (s, 1H) 8.35 (s, 1H) 8.08 (s, 1H) 9.45 (s, 1H) 8.30(m, 2H) 7.95 (m, 2H) 7.75 (m, 5H) 8.52 (s, 1H) 7.85 (d, 1H) 7.65 (m, 3H)6.17 (d, 1H) 8.05 (s, 1H) 7.72 (d, 1H) 4.04 (m, 1H) 4.80 (br, 1H) 7.82(d, 1H) 7.20 (d, 1H) 3.62 (m, 2H) 4.64 (br, 2H) 7.50 (d, 1H) 4.02 (m,1H) 2.00 (m, 1H) 4.05 (m, 1H) 7.32 (t, 1H) 3.60 (m, 2H) 0.90 (M, 6H)3.94 (m, 1H) 6.11 (d, 1H) 2.00 (m, 1H) 3.52 (m, 6H) 4.72 (s, 1H) 1.01(d, 3H) 2.01 (m, 1H) 4.10 (s, 1H) 0.90 (d, 3H) 0.93 (dd, 6H) 3.60 (m,2H) 2.01 (m, 1H) 0.99 (d, 3H) 0.92 (d, 3H) Aus- 27% 65% 85% 9% beuteSchmp. 231 Masse 420 (ES) 395 (ES) 468 (ES) 395 (ES)

Beispiel 154 155 156 157 Nr. 10.91 (s, 1H) 11.05 (s, 1H) 10.51 (s, 1H)15.5o (s, 1H) 8.38 (s, 1H) 8.34 (m, 2H) 8.22 (s, 1H) 9.50 (s, 1H) 7.90(d, 1H) 7.75 (m, 3H) 7.71 (d, 1H) 8.40 (s, 1H) 7.80 (m, 4H) 7.52 (t, 1H)7.27 (m, 1H) 8.11 (s, 1H) 7.05 (d, 1H) 4.04 (m, 1H) 6.86 (m, 2H) 7.80(d, 1H) 4.50 (s, 2H) 3.85 (s, 3H) 6.06 (s, 2H) 7.53 (d, 1H) 4.04 (m, 1H)3.65 (m, 2H) 3.96 (m, 1H) 6.16 (d, 1H) 3.62 (m, 2H) 2.00 (m, 1H) 3.62(m, 2H) 4.78 (br, 1H) 1.96 (m, 1H) 0.94 (d, 3H) 1.99 (m, 1H) 4.03 (m,1H) 0.93 (d, 3H) 0.85 (d, 3H) 0.90 (m, 6H) 3.60 (m, 2H) 0.85 (d, 3H)2.01 (m, 1H) 0.91 (dd, 6H) Aus- 90% 48% 77% 21% beute Schmp. 170 181 177196 Masse 381 (ES) 409 (ES) 394 (EI) 391 (EI)

Beispiel 158 159 * 160 * 161 * Nr. 10.80 (s, 1H) 9.65 9.65 7.92 (s, 1H)8.31 (s, 1H) (s, 1H, 1 + 2) (s, 1H, 1 + 2) 7.84 (d, 2H) 7.97 (d, 2H)8.08 8.08 7.58 (d, 2H) 7.88 (m, 3H) (s, 1H, 1 + 2) (s, 1H, 1 + 2) 3.72(m, 1H) 7.52 (m, 5H) 7.88 7.88 3.35 (m, 2H) 4.01 (m, 1H) (d, 2H, 1 + 2)(d, 2H, 1 + 2) 3.10 (m, 1H) 3.62 (m, 2H) 7.65 7.65 2.91 (m, 2H) 2.00 (m,1H) (d, 2H, 1 + 2) (d, 2H, 1 + 2) 2.00 (m, 2H) 0.91 (m, 6H) 7.15 7.151.89 (m, 2H) (s, 1H, 1 + 2) (s, 1H, 1 + 2) 1.66 (m, 4H) 6.62 (d, 1H, 2)6.62 (d, 1H, 2) 1.39 (m, 5H) 6.40 (d, 1H, 1) 6.40 (d, 1H, 1) 4.05 (m,1H, 1) 4.05 (m, 1H, 1) 3.89 (m, 1H, 2) 3.89 (m, 1H, 2) 2.30-1.202.30-1.20 (m, 15H, 1 + 2) (m, 15H, 1 + 2) Aus- 37% 21% 14% 8% beuteSchmp. 199 >300 Masse 469 (EI) 468 (EI) 468 (EI) 508 (EI)

Bsp.-Nr. 162 163 * 164 165 11.25 (s, 1H) 10.95 (s, 1H) 9.65 (s, 1H) 9.40(s, 1H) 10.72 (s, 1H) 8.54 (s, 1H) 8.47 (s, 1H) 9.47 (br, 2H) 8.10 (s,1H) 8.29 (s, 1H) 9.30 (br, 2H) 7.82 (d, 1H) 7.63 (s, 1H) 8.32 (2xs, 2H)7.45 (m, 2H) 7.43 (d, 1H) 8.08 (d, 1H) 6.20 (d, 1H) 7.07 (m, 3H) 7.88(d, 2H) 4.70 (t, 1H) 4.06 (m, 1H) 7.75 (m, 6H) 4.10 (m, 1H) 3.63 (m, 2H)7.30 (br, 4H) 3.60 (m, 2H) 1.98 (m, 1H) 6.95 (d, 1H) 3.15 (s, 3H) 0.95(d, 3H) 4.12 (m, 1H) 2.00 (m, 1H) 0.85 (d, 3H) 3.98 (m, 1H) 0.96 (d, 3H)3.30 (m, 1H) 0.89 (d, 3H) 3.10 (m, 1H) 2.69 (m, 2H) 2.25 (m, 2H) 1.80(m, 18H) 1.01 (m, 4H) 0.72 (m, 4H) Aus- 16% 33 14 51% beute Schmp. 195162-164 Masse 446 (ES) 480 (EI) 429 (ES) 462 (EI)

Beispiel 166 167 * 168 * 169 Nr. 10.90 (s, 1H) 11.15 (br, 1H) 11.30 (br,2H) 9.05 (br, 1H) 8.95 (s, 1H) 10.90 (s, 1H) 11.08 (s, 1H) 8.85 (s, 1H)7.93 (m, 2H) 9.75 (br, 2H) 10.92 (s, 1H) 8.11 (d, 1H) 7.25 (m, 3H) 8.35(s, 1H) 9.90 (s, 1H) 7.97 (s, 1H) 6.30 (s, 1H) 7.78 (m, 4H) 9.70 (s, 1H)7.47 (dd, 1H) 6.00 (d, 1H) 7.30 (br, 2H) 8.36 (2xs, 2H) 6.80 (d, 1H)4.75 (tr, 1H) 4.15 (m, 1H) 8.20 (d, 1H) 5.95 (d, 1H) 4.05 (m, 1H) 3.50(m, 5H) 7.93 (d, 2H) 4.80 (br, 2H) 3.60 (m, 2H) 2.85 (s, 6H) 7.75 (m,6H) 3.90 (m, 2H) 2.00 (m, 1H) 1.90 (m, 8H) 7.35 (br, 4H) 3.45 (m, 6H)1.00 (m, 6H) 7.10 (d, 1H) 2.00 (m, 1H) 4.15 (m, 1H) 3.98 (m, 1H) 3.64(m, 8H) 3.40 (m, 5H) 3.10 (m, 5H) 1.95 (m, 26H) Aus- 6% 16% 58% 60%beute Schmp. 256 261 Masse 390 (ES) 512 (ES) 538 (ES) 484 (ES)

Beispiel 170 * 171 172 173 Nr. 11.05 (s, 1H) 10.45 (s, 1H) 11.05 (s, 1H)8.90 (s, 1H) 10.90 (s, 1H) 8.25 (s, 1H) 8.35 (m, 2H) 8.72 (s, 1H) 10.6(br, 2H) 8.00 (br, 1H) 7.82 (d, 1H) 7.95 (s, 1H) 8.35 (2xs, 2H) 7.85 (d,2H) 7.65 (d, 2H) 7.18 (m, 1H) 8.15 (d, 1H) 7.75 (d, 2H) 7.50 (t, 1H)7.05 (dd, 1H) 7.80 (m, 8H) 7.45 (br, 1H) 4.05 (m, 1H) 6.75 (d, 1H) 7.30(br, 4H) 3.60 (m, 5H) 3.62 (m, 2H) 5.99 (d, 1H) 7.05 (m, 1H) 3.35 (m,2H) 2.00 (m, 1H) 4.74 (t, 1H) 4.25 (m, 1H) 2.80 (m, 2H) 0.96 (d, 3H)4.03 (m, 1H) 3.95 (m, 2H) 2.41 (t, 2H) 0.85 (d, 3H) 3.70 (s, 3H) 3.65(m, 1H) 1.90 (m, 2H) 3.60 (m, 2H) 3.20 (m, 10H) 2.00 (m, 1H) 1.90 (m,24H) 0.90 (m, 6H) Aus- 64% 7% 65% 40% beute Schmp. 226 164 206 144 Masse525 (ES) 488 (ES) 395 (ES) 397 (ES)

Beispiel 174 * 175 * 176 177 Nr. 11.05 (m, 3H) 11.15 (br, 1H) 8.00 (s,1H) 9.65 (s, 1H) 10.48 (s, 1H) 11.05 (s, 2H) 7.80 (m, 4H) 8.08 (s, 1H)8.38 (s, 2H) 10.65 (br, 1H) 4.48 (m, 1H) 7.85 (d, 2H) 7.80 (m, 8H) 8.30(s, 2H) 3.65 (d, 2H) 7.65 (d, 2H) 7.80 (br, 4H) 8.13 (m, 2H) 1.75 (m,1H) 7.40 (br, 1H) 7.10 (s, 1H) 7.88 (m, 8H) 1.59 (m, 2H) 7.15 (s, 2H)6.95 (s, 1H) 7.30 (br, 4H) 1.01 (d, 3H) 3.55 (m, 2H) 4.42 (m, 2H) 4.40(m, 2H) 0.92 (d, 3H) 2.55 (m, 2H) 4.18 (m, 2H) 4.00 (br, 2H) 2.15 (m,2H) 3.70-2.90 3.70-2.90 1.80 (m, 3H) (m, 10H) (m, 10H) 1.65 (m, 1H)2.40-1.60 2.40-1.40 Aus- 95% 51% 3% 8% beute Schmp. Masse 511 (ES) 511(ES) 443 (EI) 456 (EI)

Beispiel 178 179 180 181 Nr. 9.49 (s, 1H) 9.61 (s, 1H) 9.65 (s, 1H) 9.71(s, 1H) 8.25 (s, 1H) 8.08 (s, 1H) 8.11 (s, 1H) 8.06 (s, 1H) 7.80 (m, 4H)7.88 (d, 2H) 7.81 (s, 2H) 7.90 (d, 2H) 7.32 (br, 2H) 7.65 (d, 2H) 7.63(d, 2H) 7.61 (d, 2H) 4.03 (m, 2H) 7.60 (t, 1H) 7.15 (s, 2H) 7.37 (t, 1H)3.75 (m, 1H) 7.15 (s, 1H) 6.64 (d, 1H) 6.56 (d, 1H) 3.35 (m, 2H) 3.45(m, 2H) 4.28 (m, 3H) 4.66 (m, 2H) 1.80 (m, 2H) 2.40 (t, 2H) 2.00 (m, 1H)3.90 (m, 1H) 1.40 (m, 2H) 2.20 (s, 6H) 1.98 (s, 3H) 3.39 (m, 3H) 1.75(t, 2H) 0.98 (d, 3H) 2.78 (q, 2H) 0.93 (d, 3H) 1.96 (m, 4H) 1.56 (m, 2H)1.29 (m, 2H) Aus- 17% 9% 27% 24% beute Schmp. Masse 427 (EI) 428 (EI)472 (ES) 486 (ES)

Beispiel 182 183 184 185 Nr. 9.68 (s, 1H) 10.97 (s, 1H) 11.06 (s, 1H)11.01 (s, 1H) 9.47 (s, 1H) 8.30 (s, 1H) 8.04 (m, 1H) 8.38 (s, 1H) 8.10(s, 1H) 8.02 (d, 1H) 7.82 (m, 2H) 7.82 (s, 4H) 7.81 (d, 2H) 7.81 (m, 4H)7.70 (m, 2H) 7.40 (d, 1H) 7.67 (d, 2H) 7.30 (s, 2H) 7.30 (s, 2H) 7.32(s, 2H) 7.14 (s, 2H) 4.14 (m, 1H) 6.72 (m, 1H) 4.20 (m, 1H) 6.76 (m, 3H)1.80 (m, 12H) 3.75 (m, 5H) 3.70 (m, 2H) 4.47 (m, 2H) 1.88 (m, 2H) 0.97(s, 9H) 4.30 (m, 1H) 1.48 (m, 2H) 3.65 (s, 6H) 3.54 (s, 3H) 1.99 (m, 1H)0.98 (d, 3H) 0.92 (d, 3H) Aus- 57% 78% 26% 76% beute Schmp. Masse 639(ES) 439 (EI) 348 (EI) 445 (EI)

Beispiel 186 187 188 189 Nr. 9.71 (s, 1H) 7.75 (s, 1H) 10.60 (s, 1H)11.19 (s, 1H) 8.11 (s, 1H) 7.65 (d, 2H) 8.29 (s, 1H) 8.03 (d, 1H) 7.90(d, 2H) 7.58 (d, 2H) 7.79 (d, 2H) 7.88 (d, 2H) 7.70 (d, 2H) 5.82 (s, 1H)7.71 (d, 2H) 7.78 (d, 2H) 7.12 (s, 2H) 4.25 (s, 2H) 7.28 (s, 2H) 7.31(s, 2H) 6.75 (d, 1H) 3.40 (t, 2H) 6.60 (s, 1H) 6.58 (d, 1H) 4.45 (m, 1H)2.82 (t, 2H) 3.58 (s, 2H) 3.60 (m, 4H) 2.25 (m, 6H) 2.06 (s, 3H) 2.10(m, 2H) 1.20 (m, 6H) 1.90 (m, 2H) 1.78 (m, 2H) 1.55 (m, 4H) Aus- 16% 7%61% 35% beute Schmp. Masse 440 (ES) 480 (ES) 443 (EI) 321 (EI)

Beispiel 190 191 * 192 * 193 Nr. 10.61 (s, 1H) 9.67 (s, 1H) 9.63 (s, 1H)10.61 (s, 1H) 8.28 (s, 1H) 8.08 (s, 1H) 8.06 (s, 1H) 8.28 (s, 1H) 7.82(d, 2H) 7.88 (d, 2H) 7.85 (d, 2H) 7.78 (m, 4H) 7.73 (d, 2H) 7.65 (d, 2H)7.65 (d, 2H) 7.45 (d, 1H) 7.53 (br, 1H) 7.11 (s, 2H) 7.15 (s, 2H) 7.20(s, 2H) 7.25 (s, 2H) 6.35 (d, 1H) 6.55 (d, 1H) 4.30 (br, 2H) 4.25 (m,1H) 4.10 (m, 1H) 3.95 (m, 1H) 3.53 (m, 2H) 2.59 (br, 1H) 3.62 (m, 4H)3.58 (m, 4H) 1.21 (d, 3H) 2.21 (br, 1H) 2.45 (m, 4H) 2.50 (m, 4H) 1.94(m, 1H) 2.19 (m, 1H) 1.96 (m, 1H) 1.40 (m, 7H) 1.88 (m, 4H) 1.50 (m, 4H)1.65 (m, 4H) 1.30 (m, 4H) Aus- 63% 15% 17% 57% beute Schmp. Masse 437(EI) 511 (ES) 511 (EI) 403 (EI)

Beispiel 194 195 196 197 Nr. 9.89 (s, 1H) 10.98 (s, 1H) 10.39 (s, 1H)10.85 (s, 1H) 8.21 (s, 1H) 8.51 (br, 1H) 8.30 (s, 1H) 8.71 (d, 1H) 7.82(d, 2H) 8.29 (s, 1H) 8.04 (d, 2H) 8.31 (s, 1H) 7.65 (m, 3H) 7.81 (m, 4H)7.70 (d, 2H) 7.72 (d, 2H) 7.17 (br, 2H) 7.29 (br, 2H) 7.21 (br, 2H) 7.55(d, 2H) 4.30 (m, 2H) 3.45 (m, 4H) 6.55 (s, 1H) 7.30 (m, 6H) 1.68 (m, 2H)3.49 (s, 1H) 5.41 (m, 1H) 1.45 (m, 2H) 2.32 (m, 2H) 3.49 (m, 2H) 1.85(m, 2H) 2.11 (m, 2H) 1.60 (m, 5H) 1.29 (m, 1H) Aus- 26% 56% 12% 61%beute Schmp. Masse 476 (EI) 417 (EI) 450 (EI) 479 (EI)

Beispiel 198 199 196 197 Nr. 11.01 (s, 1H) 11.01 (s, 1H) 9.16 (s, 1H)8.32 (s, 1H) 8.32 (s, 1H) 8.07 (s, 1H) 8.10 (d, 1H) 8.10 (d, 1H) 7.89(d, 2H) 7.80 (m, 4H) 7.80 (m, 4H) 7.67 (d, 2H) 7.30 (br, 2H) 7.30 (br,2H) 7.15 (s, 2H) 3.70 (m, 1H) 3.70 (m, 1H) 6.45 (d, 1H) 1.80 (m, 5H)1.80 (m, 5H) 4.35 (s, 2H) 1.48 (m, 1H) 1.48 (m, 1H) 3.97 (m, 1H) 1.29(m, 2H) 1.29 (m, 2H) 3.40 (m, 4H) 1.07 (m, 1H) 1.07 (m, 1H) 2.85 (m, 1H)0.83 (d, 3H) 0.83 (d, 3H) 2.55 (m, 1H) 1.82 (m, 2H) 1.61 (m, 6H) Aus- 4%4% 7% 2% beute Schmp. Masse 439 (EI) 439 (EI) 515 (ES) 515 (ES)

Beispiel 202 203 * 204 * 205 Nr. 10.21 (s, 1H) 9.66 (s, 1H) 9.73 (s, 1H)8.18 (s, 1H) 8.08 (s, 1H) 8.11 (s, 1H) 8.10 (d, 2H) 7.90 (d, 2H) 7.82(d, 2H) 7.92 (d, 2H) 7.69 (d, 2H) 7.65 (d, 2H) 6.39 (d, 1H) 7.15 (s, 2H)7.12 (s, 1H) 4.80 (br, 1H) 6.53 (d, 1H) 6.80 (d, 1H) 4.05 (m, 1H) 3.93(m, 1H) 4.67 (m, 1H) 3.62 (m, 2H) 2.05 (m, 5H) 3.13 (m, 1H) 2.00 (m, 1H)1.51 (m, 2H) 2.86 (m, 3H) 0.99 (d, 3H) 1.15 (m, 2H) 2.18 (m, 2H) 0.92(d, 3H) 0.42 (m, 2H) 0.25 (m, 2H) Aus- 10% 2% 2% 16% beute Schmp. Masse483 (ES) 480 (EI) 480 (EI) 430 (ES)

Beispiel 206 207 208 209 Nr. 9.75 (s, 1H) 10.98 (s, 1H) 11.00 (s, 1H)9.55 (s, 1H) 8.19 (s, 1H) 8.50 (d, 2H) 8.31 (s, 1H) 8.08 (s, 1H) 7.75(d, 2H) 8.31 (s, 1H) 7.74 (m, 5H) 7.80 (d, 2H) 7.18 (d, 2H) 7.97 (d, 2H)7.21 (d, 1H) 7.60 (d, 2H) 7.17 (s, 2H) 7.78 (d, 1H) 6.80 (d, 1H) 6.58(br, 4H) 6.68 (d, 1H) 7.57 (d, 1H) 4.00 (m, 1H) 6.20 (d, 1H) 5.35 (t,1H) 7.00 (t, 1H) 3.62 (m, 2H) 4.80 (br, 1H) 4.71 (m, 1H) 4.01 (m, 1H)1.95 (m, 1H) 4.04 (m, 1H) 3.91 (m, 2H) 3.62 (m, 2H) 0.98 (d, 3H) 3.60(m, 2H) 3.65 (s, 3H) 1.97 (m, 1H) 0.90 (d, 3H) 2.00 (m, 1H) 0.98 (d, 3H)0.99 (d, 3H) 0.92 (d, 3H) 0.92 (d, 3H) Aus- 5% 55% 44% 77% beute Schmp.223 248 228 231 Masse 446 (ES) 507 (EI) 514 (EI)

Beispiel 210 211 212 71 Nr. 10.03 (s, 1H) 10.90 (s, 1H) 9.18 (s, 1H)9.66 (s, 1H) 8.38 (s, 1H) 8.40 (m, 1H) 9.05 (s, 1H) 8.08 (s, 1H) 8.14(s, 1H) 8.30 (s, 1H) 7.98 (s, 1H) 7.88 (d, 2H) 7.81 (d, 2H) 7.88 (d, 2H)7.18 (m, 2H) 7.63 (m, 3H) 7.60 (d, 1H) 7.73 (d, 2H) 6.98 (m, 2H) 7.28(t, 1H) 7.30 (m, 7H) 7.38 (br, 1H) 6.31 (m, 1H) 7.11 (s, 2H) 4.99 (s,1H) 3.45 (m, 4H) 4.45 (t, 1H) 6.88 (s, 1H) 3.42 (m, 2H) 2.38 (s, 3H)3.47 (m, 4H) 3.65 (m, 2H) 2.97 (m, 2H) 1.62 (m, 2H) 1.63 (m, 2H) 2.88(t, 2H) 1.58 (m, 2H) 1.45 (m, 2H) 1.48 (m, 2H) 1.30 (m, 4H) Aus- 86% 22%41% 77% beute Schmp. Masse 528 (CI) 429 (EI) 352 (EI) 437 (EI)

Beispiel 213 61 214 215 Nr. 12.40 (br, 1H) 12.41 (br, 1H) 8.03 (s, 1H)9.55 (s, 1H) 11.10 (s, 1H) 11.11 (s, 1H) 7.76 (m, 4h) 8.10 (s, 1H) 8.08(d, 2H) 8.10 (d, 1H) 3.70 (s, 2H) 7.80 (d, 2H) 7.79 (m, 4H) 7.80 (m, 5H)1.92 (m, 4H) 7.68 (d, 2H) 7.30 (s, 2H) 7.30 (s, 2H) 0.92 (m, 6H) 7.15(s, 2H) 4.04 (m, 1H) 4.08 (m, 1H) (in MeOD) 5.82 (s, 1H) 3.60 (m, 2H)3.63 (m, 2H) 3.74 (d, 1H) 2.07 (s, 3H) 2.50 (m, 2H) 3.52 (d, 1H) 2.00(m, 1H) 2.01 (m, 1H) 2.72 (m, 1H) 0.97 (d, 3H) 1.15 (t, 3H) 1.35 (s, 3H)0.90 (d, 3H) 0.99 (d, 3H) 0.97 (d, 3H) 0.92 (d, 3H) 0.91 (d, 3H) Aus-49% 25% 2% 9% beute Schmp. Masse 365 (EI) 379 (EI) 443 (ES) 444 (ES)

Beispiel 216 217 218 219 Nr. 10.88 (s, 1H) 10.88 (s, 1H) 11.01 (s, 1H)11.11 (s, 1H) 8.36 (s, 1H) 8.36 (s, 1H) 8.52 (br, 1H) 8.53 (m, 1H) 8.03(d2, H) 8.03 (d, 1H) 8.29 (s, 1H) 8.36 (s, 1H) 7.79 (m, 4H) 7.79 (m, 4H)7.78 (m, 4H) 7.80 (m, 4H) 7.28 (br, 2H) 7.28 (br, 2H) 7.32 (s, 2H) 7.31(s, 1H) 4.65 (m, 1H) 4.65 (m, 1H) 3.39 (m, 2H) 3.71 (m, 2H) 3.89 (m, 2H)3.89 (m, 2H) 1.70 (m, 6H) 2.65 (m, 2H) 3.71 (m, 2H) 1.15 (m, 3H) 2.19(m, 2H) 0.96 (m, 2H) Aus- 65% 34% 58% 88% beute Schmp. 239 239 238 280Masse 439 (EI) 413 (EI) 439 (EI) 416 (EI)

Beispiel 74 56 220 221 Nr. 9.67 (s, 1H) 9.70 (s, 1H) 8.92 (m, 1H) 9.66(s, 1H) 8.11 (s, 1H) 8.81 (m, 1H) 8.08 (s, 1H) 7.88 (m, 4H) 7.96 (s, 1H)7.83 (d, 2H) 6.25 (d, 1H) 7.43 (d, 2H) 7.68 (d, 2H) 4.81 (m, 1H) 6.67(d, 2H) 7.22 (t, 1H) 4.05 (m, 1H) 6.20 (m, 1H) 7.11 (s, 2H) 3.61 (m, 2H)4.38 (m, 1H) 3.95 (m, 4H) 2.01 (m, 1H) 3.48 (m, 1H) 3.48 (m, 2H) 0.97(d, 3H) 3.37 (m, 1H) 1.79 (m, 4H) 0.92 (d, 3H) 1.20 (d, 3H) 1.18 (t, 6H)Aus- 7% 17% 65% 19% beute Schmp. 285 158 166 Masse 457 (EI) 392 (EI) 354(EI) 522 (ES)

Beispiel 222 223 224 225 Nr. 9.81 (s, 1H) 9.71 (s, 1H) 9.70 (s, 1H)10.29 (s, 1H) 9.08 (s, 1H) 8.13 (s, 1H) 8.08 (s, 1H) 8.83 (m, 2H) 8.68(s, 1H) 7.89 (d, 2H) 7.88 (d, 2H) 8.51 (m, 1H) 8,35 (m, 1H) 7.66 (d, 2H)7.65 (d, 2H) 8.26 (s, 1H) 8.20 (s, 1H) 7.31 (t, 1H) 7.25 (m, 3H) 7.93(d, 2H) 8.02 (t, 1H) 7.14 (s, 2H) 6.11 (m, 1H) 7.60 (d, 2H) 7.63 (m, 5H)3.98 (m, 2H) 3.40 (m, 5H) 7.51 (d, 2H) 7.17 (s, 2H) 3.69 (s, 3H) 7.25(br, 2H) 7.03 (s, 1H) 3.64 (s, 3H) 4.90 (d, 2H) 4.82 (d, 2H) Aus- 54%23% 7% 43 beute Schmp. 300 300 243 Masse 501 (EI) 465 (EI) 434 (EI)

Beispiel 226 227 228 229 230 Nr. 10.38 (s, 1H) 10.30 (s, 1H) 10.52 (s,1H) 10.88 (s, 1H) 10.45 (s, 1H) 8.52 (br, 1H) 8.78 (m, 1H) 8.66 (m, 1H)8.92 (m, 1H) 8.20 (s, 1H) 8.23 (s, 1H) 8.36 (m, 3H) 8.28 (s, 1H) 8.33(s, 1H) 8.05 (m, 1H) 7.72 (m, 4H) 7.81 (m, 2H) 7.63 (m, 4H) 7.72 (d, 2H)7.79 (m, 4H) 7.36 (m, 1H) 7.60 (m, 4H) 7.26 (m, 6H) 7.62 (d, 2H) 7.21(s, 2H) 7.22 (s, 2H) 7.22 (br, 2H) 4.63 (d, 2H) 7.30 (m, 4H) 3.50 (m,2H) 7.03 (m, 1H) 4.94 (d, 2H) 6.89 (d, 2H) 1.83 (m, 2H) 6.95 (m, 1H)4.62 (d, 2H) 1.56 (m, 2H) 4.80 (d, 2H) 3.70 (s, 3H) Aus- 47% 41% 88% 89%58% beute Schmp. 229 287 259 233 >300 Masse 440 (CI) 434 (EI) 451 (EI)463 (EI) 466 (ES)

Beispiel 231 232 233 234 Nr. 10.3 (s, 1H) 9.28 (s, 1H) 10.48 (s, 1H)9.63 (s, 1H) 8.34 (tr, 1H) 8.0 (s, 1H) 8.25 (s, 1H) 8.12 (s, 1H) 8.2 (s,1H) 7.73 (d, 2H) 7.85 (m, 4H) 7.65 (m, 4H) 7.9 (m, 4H) 7.63 (tr, 1H)7.25 (m, 1H) 7.42 (d, 2H) 4.3 (q, 2H) 7.18 (d, 2H) 7.15 (s, 1H) 7.35(tr, 2H) 4.2 (m, 2H) 5.0 (m, 1H) 5.1 (m, 1H) 7.21 (m, 1H) 3.23 (tr, 1H)4.3 (s, 2H) 3.58 (m, 4H) 7.16 (s, 1H) 1.32 (tr, 3H) 4.14 (m, 2H) 5.35(m, 1H) 3.11 (tr, 1H) 1.55 (d, 3H) Aus- 85% 35% 33% 25% beute Schmp.Masse 330 (EI) 228 (EI) 389 (CI) 448 (ESI)

Beispiel- 235 236 237 238 Nr. Schmp. [° C.] Masse 486 (ES) 516 (ES) 504(ES) 488 (ES)

Beispiel- 239 240 241 242 Nr. Schmp. [° C.] Masse 536 (ES) 502 (ES) 484(ES) 551 (ES)

Beispiel- 243 244 245 Nr. Schmp. [° C.] Masse 516 (ES) 514 (ES) 433 (ES)

Beispiel- 246 247 248 249 Nr. Schmp. [° C.] Masse 446 (ES) 415 (EI) 504(ES) 431 (ES)

Beispiel- 250 251 252 253 Nr. Schmp. 113 231 187 [° C.] Masse 488 (ES)446 (ES) 433 (ES)

Nr. 254 255 256 257 Schmp. [° C.] Masse 399 (ES) 444 (ES) 474 (ES) 486(ES)

[0116] Compounds Nos. 159, 160, 161, 163, 167, 168, 170, 174, 175, 191,192, 203 and 204 that are identified with *) can be produced by theprocess variants that are described under Example No. 292.

EXAMPLE 258

[0117] Production of4-(5-bromo-4-morpholin-4-yl-pyrimidin-2-ylamino)-phenylsulfonamide

[0118] 202 mg (0.60 mmol) of the compound of Example No. 122 is mixedwith 1 ml of water and 0.2 g (1.2 mmol) of bromine and stirred at roomtemperature. After 24 hours, 0.2 g (1.2 mmol) of bromine is added again,and it is stirred for another 24 hours at room temperature. The solventis evaporated by means of underpressure, and the remaining residue ispurified by chromatography (Flashmaster II, DCM/MeOH 7:3). 17 mg (0.04mmol,7%) of the product is obtained as a white solid.

Beispiel- 259 260 261 262 Nr. Schmp. 205-207 202-203 [° C.] Masse MS(ES) 452, 428 (ES) 454 (M + H, 100%) Beispiel- Nr. Verbindung ESI-MS 263

434 264

434 265

477 266

477 267

552 268

552 269

[0119] Analogously to the process for the production of intermediateproducts that is described under Example 6.0, the following compoundswere also produced: Beispiel- Nr. 270 271 272

Ausbeute 47% 90% Masse ESI: ESI: ESI: MH⁺ 480 MH⁺ 432 MH⁺ 446 (18%)(100%) (100%) 478 (97%) 430 (94%) 115 (30%) 157 (43%)

[0120] Analogously to production example 1, the following compounds werealso produced:

Beis- 273 274 275 276 piel- Nr. Aus- 61% 44% 42% 68% beute Masse EI: EI:ESI: EI: M⁺ 463 (4%) M⁺ 403 (24%) MH⁺ 418 M⁺ 401 (33%) 277 (8%) 358(100%) 100% 372 (100%) 105 (100%) 277 (52%) 416 (94%) 344 (38%) 346 (8%)

Beis- 277 278 279 280 piel- Nr. Aus- 81% 58% ˜20% 30% beute Masse EI:ESI: ESI: ESI: M⁺ 431 (5%) MH⁺ 444 MH+ 494 MH+ 418 372 (100%) (100%)(75%) (100%) 291 (46%) 442 (97%) 346 (18%) 416 (97%) 115 (20%) 214 (55%)310 (27%)

Beis- 281 282 283 284 piel- Nr. Aus- 55% 43% ˜18% 35% beute Masse ESI:ESI: ESI: ESI: MH⁺ 444 MH⁺ 446 MH⁺ 416 MH⁺ 446 (100%) (100%) (100%)(100%) 442 (97%) 444 (95%) 414 (96%) 444 (90%) 214 (12%) 346 (5%) 317(4%)

Beis- 285 286 287 288 piel- Nr. Aus- 51% 46% 47% 61% beute Masse ESI:ESI: ESI. ESI. MH⁺ 520 MH⁺ 520 MH⁺ 432 MH⁺ 446 (100%) (100%) (100%)(100%) 518 (97%) 518 (97%) 430 (95%) 444 (93%) 115 (27%) 115 (23%) 346(5%) 115 (13%)

[0121] According to the production variants below, the followingcompounds are also synthesized:

[0122] 30 mg (0.0678 mmol) of compound No. 278 is dissolved in 1 ml ofmethanol/tetrahydrofuran 1:1. After adding ≈10 mg of sodium borohydride,stirring is continued for 2 hours. Then, it is quenched with ≈3-4 dropsof glacial acetic acid while being cooled, and it is concentrated byevaporation. Below, the crude product is taken up with a little water,suctioned off, rewashed with acetonitrile and dried in a vacuum at 60°C. Yield: 21 mg (70% of theory) of the desired compound.

Beispiel-Nr. 289 290 Ausbeute 52% 70% Masse EI: ESI: M⁺ 465 (5%) MH⁺ 446358 (40%) (100%) 207 (31%) 444 (93%) 117 (20%)

EXAMPLE 291

[0123] Production of the Oxime Ether-Pyrimidine Compounds of GeneralFormula I

[0124] The production of the oxime ether is carried out according to thefollowing general reaction diagram:

[0125] R⁸ and R⁹ have the meanings that are indicated in general formulaI.

[0126] Production of Example 291

[0127] 50 mg (0.12 mmol) of compound No. 283, 34 mg of hydroxylammoniumchloride and 150 mg of pulverized KOH are refluxed for 2 hours in 2 mlof ethanol. Then, it is poured onto ice water and acidified with glacialacetic acid, extracted 3 times with dichloromethane/isopropanol 4: 1,dried with magnesium sulfate and concentrated by evaporation. Theresidue is suspended with acetonitrile, suctioned off and dried at 60°C.

[0128] Yield: 28 mg (54% of theory) of the desired compound.

[0129] Mass

[0130] ESI:

[0131] MH⁺429 (29%)

[0132] 371 (61%)

[0133] 289 (91%)

[0134] Similarly produced were also the following compounds:

Besispiel-Nr. 292 293 294 Ausbeute 34% 36% 40% Masse ESI: ESI: ESI: MH+443 (95%) MH+ 485 (92%) MH⁺ 487 (91%)    445 (99%)    487 (99%)    489(89%)    373 (32%)    373 (32%)

EXAMPLE 295

[0135] Reduced Amination

[0136] 50 mg (0.12 mmol) of compound No. 283 and 7.5 mg (0.132 mmol) ofcyclopropylamine are dissolved in 2 ml of 1,2-dichloroethane. After 9.1mg (0.144 mmol) of sodium cyanoborohydride is added, it is allowed tostir for 12 more hours. Then, it is diluted withdichloromethane/isopropanol 4: 1, washed 2× with water, dried withmagnesium sulfate and concentrated by evaporation. The residue ischromatographed on silica gel with dichloromethane/methanol 95:5. Yield:18 mg (33% of theory) of the desired compound.

Ausbeute 33% Masse ESI: MH⁺ 457 (98%) 455 (93%) 249 (55%)

[0137] Produced similarly are also compounds Nos. 159, 160, 161, 163,167, 168, 170, 174, 175, 191, 203 and 204.

EXAMPLES 296 and 297

[0138] Produced similarly to Example 1 are also the following twocompounds:

Beispiel 296 297 Ausbeute 46% 47% Masse ESI: ESI: MH⁺ 432 (30%) MH⁺ 446(45%)    434 (31%)    448 (49%)    123 (100%)    123 (90%)

[0139] Production of General Formula I

[0140] 0.2 mmol of sulfonic acid fluoride is introduced into the reactorof a synthesizer. 1.0 ml of solvent, preferably 2-butanol, is added. 0.2ml (0.2 mmol) of DMAP—dissolve in a solvent, for example DMSO or2-butanol—and 0.2 ml (0.2 mmol) of the amine, dissolved in 2-butanol,are added in succession via a pipette. The reaction mixture is thenstirred for 20 hours at 80° C. After the reaction is completed, thecrude product is pipetted off, and the reactor is rewashed with 1.0 mlof THF. The solution of the crude product is then concentrated byevaporation and purified by HPLC.

[0141] The compounds below were produced: Beispiel- Nr. VerbindungMolgewicht ESI-MS 298

526.4968 526/528 299

562.5298 562/564 300

624.6006 624/626 301

501.4471 501/503 302

538.4682 538/540 303

588.4465 588/590 304

528.5126 528/530 305

542.5394 542/544 306

556.5662 556/558 307

570.593 570/572 308

510.4106 510/512 309

588.4465 588/590 310

548.503 548/550 311

555.4949 555/557 312

500.459 500/502 313

514.4858 514/516 314

515.4739 515/517 315

557.5543 557/559 316

470.3896 470/472 317

551.5069 551/553 318

534.4762 534/536 319

568.9213 568/570 320

524.4374 524/526 321

543.4839 543/545 322

488.4044 488/490 323

526.4776 526/528 324

564.502 564/566 325

527.4849 527/529 326

541.5117 541/543 327

538.4395 538/540 328

541.5117 541/543 329

521.4375 521/523 330

538.4395 538/540 331

521.4375 521/523 332

550.4752 550/552 333

550.4752 550/552 334

613.5551 613/615 335

534.4762 534/536 336

512.47 512/514 337

548.503 548/550 338

610.5738 610/612 339

487.4203 487/489 340

524.4414 524/526 341

574.4197 574/576 342

514.4858 516/514 343

528.5126 528/530 344

542.5394 542/544 345

556.5662 556/558 346

496.3838 496/498 347

574.4197 574/576 348

534.4762 534/536 349

541.4681 541/543 350

486.4322 486/488 351

500.459 500/502 352

501.4471 501/503 353

543.5275 543/545 354

456.3628 456/458 355

537.4801 537/539 356

520.4494 520/522 357

554.8945 554/556 358

510.4106 510/512 359

529.4571 529/531 360

474.3776 474/476 361

512.4508 541/514 362

550.4752 550/552 363

513.4581 513/515 364

527.4849 527/529 365

524.4127 524/526 366

527.4849 527/529 367

507.4107 507/509 368

524.4127 524/526 369

507.4107 507/509 370

536.4484 536/538 371

536.4484 536/538 372

599.5283 599/601 373

520.4494 520/522 374

512.47 512/514 375

548.503 548/550 376

610.5738 610/612 377

524.4414 524/526 378

574.4197 574/576 379

514.4858 514/516 380

528.5126 528/530 381

542.5394 542/544 382

496.3838 496/498 383

574.4197 574/576 384

534.4762 534/536 385

541.4681 541/543 386

486.4322 486/488 387

500.459 500/502 388

501.4471 501/503 389

543.5275 543/545 390

537.4801 537/539 391

520.4494 520/522 392

554.8945 554/556 393

510.4106 510/512 394

529.4571 529/531 395

474.3776 474/476 396

512.4508 512/514 397

513.4581 513/515 398

527.4849 527/529 399

524.4127 524/526 400

527.4849 527/529 401

507.4107 507/509 402

524.4127 524/526 403

507.4107 507/509 404

536.4484 526/538 405

536.4484 536/538 406

599.5283 599/601 407

520.4494 520/522 408

529.4419 529/531 409

534.4762 534/536 410

596.547 596/598 411

473.3935 473/475 412

510.4146 510/512 413

560.3929 560/562 414

500.459 500/502 415

514.4858 514/516 416

528.5126 528/530 417

482.357 482/484 418

560.3929 560/562 419

520.4494 520/522 420

527.4413 527/529 421

472.4054 472/474 422

486.4322 486/488 423

487.4203 487/489 424

529.5007 529/531 425

523.4532 523/525 426

506.4226 506/508 427

540.8677 540/542 428

496.3838 496/498 429

515.4303 515/517 430

460.3508 460/462 431

498.424 498/500 432

499.4313 499/501 433

513.4581 513/515 434

510.3859 510/512 435

513.4581 513/515 436

493.3839 493/495 437

510.3859 510/512 438

493.3839 493/495 439

522.4216 522/524 440

522.4216 522/524 441

585.5015 585/587 442

506.4226 506/508 443

515.4151 515/517 444

416.30 416/418

[0142] Pyrimidine-Sulfonyl Fluorides of General Formula I

[0143] The production of the pyrimidine-sulfonic acid fluorides iscarried out analogously to the production of the sulfonic acid amides.

Schmelzpunkt Beispiel- Molge- [° C.] Nr. Verbindung wicht und ESI-MS 445

405,25 217-220 405/407 446

419,27 196-202 419/421 447

419,27 165-196 419/421 448

433,30 198-204 433/435 449

433,30 144-149 433/435 450

447,33 219-222 447/449

[0144] Similarly produced to the above-described examples were also thefollowing para-compounds: Beispiel-Nr. Verbindung MolekulargewichtESI-MS 451

498,4432 498/500 452

534,4762 534/536 453

596,547 596/598 454

473,3935 473/475 455

510,4146 510/512 456

560,3929 560/562 457

500,459 500/502 458

514,4858 514/516 459

528,5126 528/530 460

542,5394 542/544 461

560,3929 560/562 462

520,4494 520/522 463

527,4413 527/529 464

472,4054 472/474 465

486,4322 486/488 466

529,5007 529/531 467

442,336 442/444 468

523,4532 523/525 469

506,4226 506/508 470

540,8677 540/542 471

496,3838 496/498 472

515,4303 515/517 473

460,3508 460/462 474

498,424 498/500 475

536,4484 536/538 476

499,4313 499/501 477

513,4581 513/515 478

510,3859 510/512 479

513,4581 513/515 480

493,3839 493/495 481

510,3859 510/512 482

493,3839 493/495 483

522,4216 522/524 484

522,4216 522/524 485

585,5015 585/587 486

506,4226 506/508 487

515,4151 515/517 488

512,47 512/514 489

548,503 548/550 490

610,5738 610/612 491

487,4203 487/489 492

524,4414 524/526 493

574,4197 574/576 494

514,4858 516/514 495

528,5126 528/530 496

542,5394 542/544 497

556,5662 556/558 498

496,3838 496/498 499

574,4197 574/576 500

534,4762 534/536 501

541,4681 541/543 502

486,4322 486/488 503

500,459 500/502 504

501,4471 501/503 505

543,5275 543/545 506

456,3628 456/458 507

537,4801 537/539 508

520,4494 520/522 509

566,4742 510

554,8945 554/556 511

510,4106 510/512 512

529,4571 529/531 513

474,3776 474/476 514

512,4508 512/514 515

550,4752 550/552 516

513,4581 513/515 517

527,4849 527/529 518

524,4127 524/526 519

527,4849 527/529 520

507,4107 507/509 521

524,4127 524/526 522

507,4107 507/509 523

536,4484 536/538 524

536,4484 536/538 525

599,5283 599/601 526

520,4494 520/522 527

529,4419 529/531

[0145] Separation of Diastereomer Mixtures of the Compounds According tothe Invention

[0146] Separation in the Example of the Diastereomer Mixture of CompoundNo. 275

[0147] The diastereomer mixture was separated in the two correspondingracemates (A and B) by means of HPLC.

Racemate B Racemate A NMR DMSO-d6: DMSO-d6: 9.68, s, 1H 9.68, s, 1H8.12, s, 1H 8.11, s, 1H 7.87, d, 2H 7.85, d, 2H 7.70, d, 2H 7.69, d, 2H7.14, s, 2H 7.16, s, 2H 6.15, d, 1H 6.35, d, 1H 5.01, d, 1H 4.90, d, 1H4.10, m, 1H 4.08, m, 1H 3.80, m, 1H 3.80, m, 1H 1.22, d, 3H 1.18, d, 3H1.1, d, 3H 1.12, d, 3H

[0148] Below, racemates A and B in each case were separated by means ofchiral HPLC. Conditions: Column: Chiralpak AD (10 μm) 250 × 4.6 mmEluant: Hexane/ethanol 80:20 Flow: 1.0 ml/min Detection: PDA 300 nmRetention times: Enantiomer A1 - 16.6 minutes Enantiomer A2 - 19.6minutes Enantiomer B1 - 16.0 minutes Enantiomer B2 - 17.8 minutes

[0149] Production of the intermediate stages preferably used for thesynthesis of the compounds of general formula I according to theinvention.

EXAMPLE 1.0

[0150] Production ofN-(2-chloro-5-fluoro-4-pyrimidinyl)-N-2-propynylamine

[0151] 11.1 g (66 mmol) of 2,4-dichloro-5-fluoropyrimidine is dissolvedin 60 ml of acetonitrile, and 10.2 ml (73 mmol) of triethylamine and 6.0ml (86 mmol) of propynylamine are added. The reaction mixture is stirredovernight at room temperature and then poured into water. The mixture isextracted by means of ethyl acetate, the combined organic phases aredried on MgSO₂, and the solvent is evaporated by means of underpressure.After the remaining material is recrystallized with diisopropylether/hexane, the yield is 10.6 g (87% of theory) of the product.

5-H 8.18 (3.3 Hz, 1H) Solvent: DMSO 4CH 4.14 (dd, 2H) Yield: 87% 3.20(t, 1H) Melting point: 96° C. NH 8.65 (tb, 1H)

[0152] The 4-(diaminocyclohexyl) derivatives that are described beloware synthesized via reductive aminations of the described ketoderivative with use of triacetoxy borohydride (Abdel-Magid, Carson,Harris, Maryanoff, Sha, J. Org. Chem. 1996, 61, 3849). The ketoderivative is obtained by TPAP oxidation (Griffith, Ley, AldrichimicaActa 1990, 23, 13) of the corresponding alcohol.

[0153] Similarly produced are also the following intermediate compounds:

Beispiel-Nr. 1.1 1.2 1.3 1.4 Lösemittel CDCl₃ DMSO DMSO DMSO 5-H 7.87(s,1H) 8.34(s, 1H) 8.24(s, 1H) 8.23(s, 1H) 4CH 4.32(dd, 2H) 4.48(q, 1H)3.59(td, 2H) 3.21(t, 2H) 2.30(t, 1H) 1.93(dq, 2H) 2.78(t, 2H) 1.10(mc,1H) 0.92(t, 3H) 7.57(s, 1H) 0.42(mc, 2H) 5CH 2.03(s, 3H) 3.66(s, 3H)6.85(s, 1H) 0.37(mc, 2H) 7.90(tb, 1H) 7.84(t, 1H) NH 4.91(sb, 1H)7.69(d, 1H) 11.92(sb, 1H) Ausbeute 80% 42% 33% 74% Schmp. 121-121.5° C.73° C. 90° C.

Beispiel-Nr. 1.5 1.6 1.7 1.8 Lösemittel DMSO DMSO DMSO DMSO 6-H 8.26(s,1H) 8.26(s, 1H) 8.27(s, 1H) 8.37(s, 1H) 4CH 3.59(mc, 2H) 3.58(mc, 2H)3.58(sb, 4H) 4.40(m, 1H) 3.90(mc, 1H) 3.97(mc, 1H) 4.14(mc, 1H) 3.49(dd,1H) 1.98(mc, 1H) 1.96(mc, 1H) 3.33(dd, 1H) 0.94(d, 3H) 0.92(d, 3H)3.26(s, 3H) 0.86(d, 3H) 0.84(d, 3H) 1.15(d, 3H) OH 4.67(mb, 1H) 4.74(t,1H) 4.78(sb, 2H) NH 6.75(sb, 1H) 6.87(d, 1H) 6.73(sb, 1H) 7.29(d, 1H)Ausbeute 82% 91% 41% 74% Schmp. 113-114° C. 121-122° C. 155-156° C. Öl

Beispiel-Nr. 1.9 1.10 Lösemittel DMSO DMSO 6-H 8.24(s, 1H) 8.36(s, 1H)4CH 3.49(q, 2H) 4.14(d, 2H) 2.50(t, 2H) 3.18(t, 1H) 2.42(t, 4H) 3.56(t,4H) OH NH 7.57(sb, 1H) 8.40(s, 1H) Ausbeute 31% 73 Schmp. 118-119° C.103-104° C.

Beispiel-Nr. 1.11 1.12 1.13 1.14 Lösemittel DMSO DMSO DMSO DMSO 6-H8.30(s, 1H) 8.32(s, 1H) 8.29(s, 1H) 8.24(s, 1H) 4.46(dq, 1H) 5.04(q, 1H)3.7-3.9(2H) 4.25(m, 1H) 1.38(d, 3H) 2.39(m, 2H) 5.19(m, 1H) 3.48(m, 2H)7.2-7.4(5H) NH 7.60(sb, 1H) 4.31(q, 1H) 7.72(d, 1H) 1.86(m, 2H) 5.09(t,1H) OH 7.29(sb, 1H) 4.40(t, 1H) 2.43(m, 2H) 7.21(d, 1H) 8.13(d, 1H)2.03(s, 3H) 7.13(d, 1H) 4.88(t, 1H) Ausbeute 87% 63% 99% 78% Schmp. 234°C. 210° C. 152-153° C. 130° C. Zers. Zers.

Beispiel-Nr. 1.15 1.16 1.17 Lösemittel DMSO DMSO DMSO 6-H 8.20(s, 1H)8.21(s, 1H) 8.22(s, 1H) 3.55(m, 2H) 3.33(q, 2H) 3.39(q, 2H) 4.22(m, 1H)1.53(m, 4H) 2.26(t, 2H) 5.03(m, 2H) 1.28(m, 2H) 1.79(q, 2H) 7.1-7.4(5H)2.29(t, 2H) NH 6.53(d, 1H) 7.74(t, 1H) 7.78(t, 1H) 5.93(d, 1H) 12.11(sb,1H) Ausbeute 93% 99% 11% Schmp. Öl Öl Öl

Beispiel-Nr. 1.18 1.19 1.20 Ausbeute 86% 64% 87% Masse ESI: ESI: CI: MH⁺297(2%) MH⁺311(2%) M + 354(100%) 266(22%) 248(20%) 352(72%) 234(30%)236(18%) 308(54%)

Beispiel-Nr. 1.21 1.22 1.23 Ausbeute 26% ˜20% 89% Masse EI: NMR, CDCl3EI: M⁺ 327(10%) 8, 16(s, 1H) M⁺ 265(15%) 222(36%) 6, 55(s, 1H) 236(100%)105(100%) 4, 43(d, 2H) 209(18%) 1, 29(s, 9H)

Beispiel-Nr. 1.24 1.25 1.26 Ausbeute 75% 70% 83% Masse CI: CI ESI: M⁺384 M⁺ 384(100%) 319  3% (100%) 212(21%) 278 100% 212(21%) 91(7%) 220 68%  91(7%)

Beispiel-Nr. 1.27 Ausbeute 98% Masse ESI: MH^(+ 296(90%)) 298(100%)210(12%)

EXAMPLE 2.0

[0154] Production of5-Bromo-2-chloro-4-(4,4,4-trifluorobutoxy)pyrimidine

[0155] 3.19 g (14 mmol) of 5-bromo-2,4-dichloropyrimidine is mixed with8.06 g (63 mmol) of 4,4,4-trifluorobutanol, and 0.74 ml (8.4 mmol) oftrifluoromethanesulfonic acid is slowly added to it. The reactionmixture is stirred overnight at room temperature and then poured intowater. The mixture is extracted by means of ethyl acetate, the combinedorganic phases are dried on MgSO₂, and the solvent is evaporated bymeans of underpressure. The product is always contaminated with varyingamounts of 2,4-bisalkoxypyrimidine. The remaining material is thereforepurified by means of gradient chromatography with silica gel as acarrier medium (eluant: hexane and hexane/ethyl acetate at a 9:1 ratio).This process results in a yield of 1.70 g (38%) and also yields 1.93 g(34%) of 5-bromo-2,4-bis-(4,4,4-trifluorobutoxy)pyrimidine (startingcompound).

5-H 8.74 (s, 1H) Chromatography: H to H/EA 9:1 4C 4.48 (t, 2H) Yield:38% H 2.00 (mc, 2H) Melting point: 66.5-67.5° 2.44 (mc, 2H) 5C H-

[0156] Similarly produced are also the following compounds:

Beispiel-Nr. 2.1 2.2 CDCl₃ DMSO 5-H 8.49 (s, 1H) 8.75 (s, 1H) 4CH 5.10(d, 2H) 4.05 (mc, 2H) 3.79 (mc, 2H) 3.60 (mc, 2H) 5CH 2.59 (t, 1H) 3.48(mc, 2H) 3.40 (t, 2H) 1.07 (t, 3H) Chrom. H to DCM to DCM/ H/EA 4:1 MeOH95:5 Ausbeute 78% 11% Schmp. 55° C. Öl

[0157] Analogously to process examples 1 and 2, the followingintermediate products are also produced:

Beispiel- 1-2.1 1-2.2 1-2.3 1-2.4 Nr. Löse- DMSO DMSO DMSO DMSO Mittel8.26 (s, 1H) 8.26 (s, 1H) 8.29 (s, 1H) 8.28 (s, 1H) 6.65 (d, 1H) 6.65(d, 1H) 6.32 (s, 1H) 7.09 (d, 1H) 4.70 (t, 1H) 4.70 (t, 1H) 4.89 (t, 3H)5.05 (d, 1H) 4.10 (dt, 1H) 4.10 (dt, 1H) 3.74 (d, 6H) 3.95 (m, 1H) 3.65(at, 2H) 3.65 (at, 2H) 3.60 (m, 5H) 0.90 (s, 9H) 0.90 (s, 9H) 1.30 (s,3H) 1.28 (s, 3H) Aus- 49% 70% 16% 92% beute Masse 309 (EI) 309 (EI) 314(EI) 354 (EI)

Beispiel- 1-2.5 1-2.6 1-2.7 1-2.8 Nr. Löse- DMSO DMSO DMSO DMSO mittel8.15 (s, 1H) 8.22 (s, 1H) 8.28 (s, 1H) 8.22 (s, 1H) 7.25 (t, 1H) 4.82(t, 1H) 6.29 (s, 1H) 7.23 (d, 1H) 3.16 (s, 2H) 4.49 (br, 1H) 5.31 (t,1H) 4.60 (d, 1H) 1.90 (s, 3H) 3.85 (m, 1H) 3.39 (d, 2H) 3.85 (m, 1H)1.61 (q, 6H) 3.76 (m, 1H) 1.39 (s, 6H) 3.35 (m, 1H) 1.41 (s, 6H) 3.54(m, 1H) 1.80 (m, 4H) 3.40 (m, 1H) 1.53 (m, 2H) 1.93 (m, 3H) 1.20 (m, 2H)1.80 (m, 1H) Aus- 70% 75% 46% 24% beute Masse 357 (EI) 293 (EI) 281 (EI)305 (EI)

Beispiel- 1-2.9 1-2.10 1-2.11 1-2.12 Nr. Löse- DMSO DMSO DMSO DMSOmittel 8.38 (s, 1H) 8.22 (s, 1H) 8.21 (s, 1H) 8.31 (s, 1H) 4.81 (br, 1H)7.05 (d, 1H) 7.06 (d, 1H) 7.32 (d, 1H) 3.96 (m, 2H) 4.82 (t, 1H) 4.81(t, 1H) 4.35 (s, 1H) 3.72 (m, 1H) 4.18 (m, 1H) 4.22 (m, 1H) 3.68 (s, 3H)3.30 (m, 2H) 3.42 (m, 2H) 3.47 (m, 2H) 2.32 (m, 1H) 1.81 (m, 2H) 1.15(d, 3H) 1.51 (m, 2H) 0.90 (dd, 6H) 1.48 (m, 2H) 1.37 (m, 1H) 0.88 (m,6H) Aus- 19% 71% 99% 77% beute Masse 292 (EI) 266 (EI) 308 (EI) 322 (ES)

Beispiel- 1-2.13 1-2.14 1-2.15 1-2.16 Nr. Löse- DMSO DMSO DMSO DMSOmittel 8.41 (s, 1H) 8.25 (s, 1H) 8.19 (s, 1H) 8.19 (s, 1H) 8.11 (s, 1H)4.53 (m, 1H) 7.65 (t, 1H) 7.30 (d, 1H) 4.28 (t, 2H) 3.88 (m, 2H) 3.18(t, 2H) 3.65 (m, 1H) 3.70 (dd, 1H) 1.62 (m, 6H) 1.68 (m, 5H) 3.62 (dd,1H) 1.16 (m, 3H) 1.25 (m, 4H) 2.16 (m, 1H) 0.90 (m, 2H) 0.78 (d, 3H)2.02 (m, 1H) 7.56 (d, 1H) Aus- 46% 72% 68% 31% beute Masse 390 (FAB) 277(EI) 303 (EI) 305 (EI)

Beispiel- 1-2.17 1-2.18 1-2.19 1-2.20 Nr. Löse- DMSO DMSO DMSO DMSOmittel 8.21 (s, 1H) 8.35 (t, 1H) 8.21 (s, 1H) 8.20 (s, 1H) 7.22 (d, 1H)8.19 (s, 1H) 7.81 (t, 1H) 7.71 (t, 1H) 3.88 (m, 1H) 3.40 (m, 2H) 3.41(dd, 2H) 4.45 (br, 1H) 1.70 (m, 4H) 2.97 (p, 1H) 2.31 (m, 10H) 3.40 (m,4H) 1.50 (m, 12H) 2.22 (m, 4H) 2.13 (s, 3H) 1.60 (m, 2H) 1.28 (m, 1H)2.08 (dd, 1H) 1.70 (p, 2H) 1.44 (m, 2H) 1.01 (m, 2H) 1.70 (m, 6H) 0.82(d, SH) Aus- 22% 32% 28% 98% beute Masse 303 (EI) 320 (EI) 349 (EI) 281(EI)

Beispiel- 1-2.21 1-2.22 1-2.23 1-2.24 Nr. Löse- DMSO DMSO DMSO DMSOmittel 8.25 (s, 1H) 8.25 (s, 1H) 8.20 (s, 1H) 8.21 (s, 1H) 8.08 (d, 1H)7.38 (d, 1H) 7.28 (d, 1H) 7.24 (d, 1H) 7.35 (m, 5H) 4.44 (m, 1H) 4.19(m, 1H) 7.02 (t, 1H) 5.30 (m, 1H) 2.60 (m, 2H) 2.40 (m, 6H) 4.40 (m, 1H)4.81 (t, 1H) 2.24 (m, 2H) 1.50 (m, 4H) 3.92 (m, 1H) 3.45 (m, 2H) 2.07(m, 2H) 1.15 (d, 3H) 2.95 (q, 2H) 2.05 (m, 2H) 1.90 (m, 2H) 0.91 (t, 6H)1.95 (m, 2H) 1.82 (m, 2H) 1.59 (m, 2H) 1.3 (m, 6H) 0.82 (t, 3H) Aus- 97%58% 52% 70% beute Masse 343 (EI) 304 (ES) 348 (EI)

Beispiel- 1-2.25 1-2.26 1-2.27 1-2.28 Nr. Löse- DMSO DMSO DMSO DMSOmittel 8.22 (s, 1H) 8.25 (s, 1H) 8.22 (s, 1H) 7.21 (d, 1H) 6.87 (d, 1H)7.28 (d, 1H) 3.82 (m, 1H) 4.02 (m, 1H) 3.85 (m, 1H) 2.45 (m, 4H) 2.45(m, 4H) 2.19 (s, 6H) 2.22 (m, 1H) 2.22 (m, 1H) 2.15 (m, 1H) 1.78 (m, 8H)1.78 (m, 8H) 1.82 (m, 4H) 1.45 (m, 6H) 1.45 (m, 6H) 1.50 (m, 2H) 1.25(m, 2H) Aus- n.b. 26% 23% 51% beute Masse 344 (EI) 374 (EI) 374 (EI) 334(EI)

Beispiel- 1-2.29 1-2.30 1-2.31 1-2.32 Nr. Löse- DMSO DMSO DMSO DMSOmittel 8.22 (s, 2H) 8.21 (s, 1H) 8.21 (s, 1H) 8.71 (s, 1H) 7.28 (d, 1H)7.18 (d, 1H) 7.22 (d, 1H) 5.32 (m, 1H) 7.10 (d, 1H) 4.62 (s, 1H) 4.65(s, 1H) 3.82 (m, 2H) 4.00 (m, 1H) 4.20 (m, 1H) 4.15 (m, 1H) 3.55 (m, 2H)3.85 (m, 1H) 3.95 (m, 1H) 3.85 (m, 1H) 2.00 (m, 2H) 2.19 (s, 6H) 2.75(dd, 1H) 2.78 (m, 1H) 1.70 (m, 2H) 2.17 (s, 6H) 2.50 (m, 2H) 2.60 (m,1H) 2.15 (m, 1H) 2.31 (dd, 1H) 2.38 (dd, 1H) 2.00 (m, 1H) 2.15 (s, 1H)1.95 (m, 3H) 1.82 (m, 8H) 2.00 (m, 1H) 1.80 (m, 2H) 1.50 (m, 6H) 1.82(m, 4H) 1.52 (m, 3H) 1.25 (m, 2H) 1.55 (m, 5H) 1.20 (m, 2H) Aus- 13% 35%21% 40% beute Masse 334 (EI) 374 (EI) 374 (EI) 292 (EI)

Beispiel- 1-2.33 1-2.34 1-2.35 1-2.36 Nr. Löse- DMSO CDCI3 DM50 CDCI3mittel 8.50 (s, 1H) 8.08 (s, 1H) 8.23 (s, 1H) 8.11 (s, 2H, 1 + 2) 4.10(m, 2H) 6.04 (m, 1H) 7.27 (d, 1H) 5.55 (m, 1H, 1) 3.72 (m, 1H) 5.71 (br,1H) 7.04 (t, 1H) 5.29 (m, 1H, 2) 3.30 (m, 2H) 4.48 (d, 2H) 4.46 (m, 1H)4.25 (m, 1H, 1) 1.75 (m, 2H) 3.71 (s, 3H) 3.95 (m, 1H) 3.98 (m, 1H, 2)1.35 (m, 2H) 2.25 (s, 3H) 2.94 (m, 2H) 3.72 (m, 8H, 1 + 2) 1.92 (m, 4H)2.65 (m, 8H, 1 + 2) 1.62 (m, 2H) 1.70 1.32 (m, 6H) (m, 18H, 1 + 2) 0.84(t, 3H) Aus- 3% 30% 70% 66% beute Masse 291 (EI) 300 (ES) 405 (ES) 375(ES)

Beispiel- 1-2.37 1-2.38 1-2.39 1-2.40 Nr. Löse- CDCl3 CDCl3 DMSO DMSOmittel 8.14 (s, 1H) 8.20 (s, 1H) 8.22 (s, 1H) 8.22 (s, 1H) 5.41 (m, 1H)7.71 (m, 1H) 6.35 (s, 1H) 7.12 (d, 1H) 4.49 (m, 1H) 7.30 (m, 6H) 5.19(t, 1H) 4.10 (m, 1H) 2.44 (m, 6H) 4.97 (s, 2H) 3.54 (d, 2H) 2.20 (m, 1H)1.79 (m, 2H) 3.00 (m, 2H) 2.00 (m, 2H) 1.89 (m, 1H) 1.40 (m, 8H) 1.75(m, 4H) 1.35 (m, 8H) 1.53 (m, 2H) Aus- 58% 77% 48% 60% beute Masse 304(ES) 427 (ES) 308 (EI) 301 (EI)

Beispiel- 1-2.41 1-2.42 1-2.43 1-2.44 Nr. Löse- DMSO DMSO DMSO DMSOmittel 8.19 (s, 1H) 8.21 (s, 1H) 8.28 (s, 1H) 8.41 (s, 1H) 7.21 (d, 1H)7.03 (d, 1H) 3.62 (q, 4H) 8.15 (t, 1H) 4.03 (m, 1H) 4.83 (t, 1H) 1.18(t, 6H) 4.21 (td, 2H) 1.60 (m, 12H) 4.13 (m, 1H) 3.47 (m, 2H) 1.12 (d,3H) Aus- 73% 61% 13% 21% beute Masse 303 (EI) 267 (EI) 265 (EI) 339 (EI)

Beispiel- 1-2.45 1-2.46 1-2.47 1-2.48 Nr. Löse- DMSO DMSO DMSO DMSOmittel 8.36 (s, 1H) 8.26 (s, 1H) 8.32 (t, 1H) 8.15 (s, 1H) 6.56 (s, 1H)8.06 (d, 1H) 8.15 (s, 1H) 7.06 (d, 1H) 3.81 (s, 1H) 7.30 (m, 5H) 3.40(m, 2H) 4.65 (br, 1H) 2.28 (m, 2H) 5.29 (m, 1H) 2.34 (m, 2H) 3.79 (m,1H) 1.83 (m, 2H) 4.81 (t, 1H) 2.18 (s, 6H) 3.52 (m, 1H) 1.58 (m, 6H)3.42 (m, 2H) 1.69 (m, 2H) 1.86 (m, 2H) 2.10 (m, 2H) 1.61 (m, 2H) 1.25(m, 4H) Aus- 84% 97% 22% 53% beute Masse 314 (EI) 343 (EI) 294 (EI) 307(EI)

Beispiel- 1-2.49 1-2.50 1-2.51 1-2.52 Nr. Löse- DMSO DMSO DMSO mittel8.29 (s, 1H) 8.18 (s, 1H) 8.29 (s, 1H) 8.38 (s, 1H) 6.05 (s, 1H) 7.25(d, 1H) 6.18 (s, 1H) 7.28 (d, 1H) 5.18 (m, 1H) 4.15 (m, 1H) 5.15 (t, 1H)5.28 (t, 1H) 3.54 (s, 2H) 2.40 (m, 6H) 3.70 (m, 1H) 4.65 (m, 1H) 1.92(m, 2H) 1.50 (m, 4H) 3.49 (m, 1H) 3.86 (m, 2H) 1.70 (m, 2H) 1.17 (d, 3H)2.60 (m, 1H) 3.65 (s, 3H) 0.90 (dd, 6H) 0.92 (d, 3H) 0.83 (d, 3H) Aus-16% 52% 27% 63% beute Masse 308 (EI) 350 (EI) 308 (EI) 309 (EI)

Beispiel- 1-2.53 1-2.54 1-2.55 Nr. Löse- DMSO DMSO DMSO mittel 8.22 (s,1H) 7.75 (s, 1H) 8.18 (s, 1H) 7.65 (t, 1H) 6.55 (d, 1H) 7.69 (t, 1H)7.30 (m, 6H) 4.54 (m, 1 4.32 (br, 1H) 5.01 (s, 2H) 3.35 (m, 4H) 3.38 (m,2H) 1.40 (m, 6H) 3.04 (m, 2H) 1.68 (m, 2H) Aus- 77% 50% 43% beute Masse398 (EI) 229 (EI) 295 (EI)

EXAMPLE 3.0

[0158] Production of Amines

[0159] 4.5 g (20 mmol) of 2-bromobutyraldehyde diethyl acetyl(Pfaltz-Bauer Company) and 5.2 g (80 mmol) of sodium azide are stirredfor 5 days in 15 ml of DMF at 100° C. Then, it is poured onto colddilute sodium bicarbonate solution, extracted 3× with ether, the organicphase is dried with magnesium sulfate and concentrated by evaporation:raw yield 1.87 g (50% of theory).

[0160] 936 mg of the crude product is dissolved in 50 ml of methanol,mixed with palladium on carbon (10%) and stirred for 12 hours under H₂atmosphere. After the catalyst is filtered off and after concentrationby evaporation, 457 mg (57% of theory) of the desired amine remains.

Beispiel- 3.0 3.1 3.2 3.3 Nr. Ausbeute 50% 57% 50% 71% NMR 4.38 (d, 1H)4.19 (d, 1H) 4.38 (d, 1H) 4.25 (d, 1H) CDCl3 3.72 (m, 2H) 3.68 (m, 2H)3.58 (m, 2H) 3.5 (m, 1H) 3.6 (m, 2H) 3.52 (m, 2H) 3.5 (m, 1H) 3.42 (s,3H) 3.25 (m, 1H) 2.7 (m, 1H) 3.49 (s, 3H) 3.41 (s, 3H) 1.7 (m, 1H) 1.60(m, 1H) 3.43 (s, 3H) 3.40 (m, 1H) 1.46 (m, 1H) 1.25 (m, 1H) 3,39 (s, 3H)3.08 (m, 1H) 1.25 (trtr, 6H) 1.2 (trtr, 6H) 1.0 (tr, 3H) 0.95(tr, 3H)

EXAMPLE 4.0

[0161] Production of the Free Aldehydes

[0162] 148 mg (0.5 mmol) of intermediate product compound 1.18 isdissolved in 1 ml of glacial acetic acid. At room temperature, 0.5 ml ofdN hydrochloric acid is added, and it is stirred for 12 hours. Forworking-up, it is poured onto ice water and carefully neutralized withpulverized sodium bicarbonate. Then, it is extracted 3× with ethylacetate, the organic phase is dried with magnesium sulfate andconcentrated by evaporation, crude product 104 mg (83% of theory) of thealdehyde of compound 4.0. The crude product can be used without furtherpurification.

Beispiel- 4.1 4.0 4.2 4.3 Nr. Aus- 82% 83% 89% 79% beute Masse ESI: ESI:ESI: ESI: MH⁺ 278 MH⁺ 250 MH⁺ 266 MH+ 294 (39%) (9%) (8%) (10%) 210(100%)

EXAMPLE 5.0

[0163] Production of Ketones

[0164] 100 mg (0.356 mmol) of compound 6.0 and 126 mg ofN-methylmorpholine-N-oxide are dissolved in 5 ml of dichloromethane andstirred for 10 minutes with pulverized molecular sieve (4 A). Then, 6 mgof tetrapropylammonium perruthenate is added, and it is stirred for 4more hours at room temperature. After concentration by evaporation, itis chromatographed on silica gel (hexane/ethyl acetate 4:1>2:1). Yield:75 mg (76% of theory) of the ketone of compound 5.0.

Beispiel- 5.0 Nr. Aus- 76% beute Masse ESI: MH⁺ 280 (100%) 200 (37%) 156(30%)

EXAMPLE 6.0

[0165] Production of Alcohols

[0166] 265 mg (1 mmol) of compound 4.2 is dissolved in 20 ml oftetrahydrofuran. While being cooled in an ice bath, 5 equivalents ofmethylmagnesium bromide (3 molar solution in ether) is added inportions. Then, it is stirred for 3 more hours at room temperature andthen quenched with water while being cooled. Then, it is mixed withammonium chloride solution, extracted 3× with ethyl acetate, the organicphase is dried with magnesium sulfate and concentrated by evaporation.Flash chromatography (hexane/ethyl acetate 2:1) yields 213 mg (76% oftheory) of the alcohol of compound 6.0.

[0167] ESI:MH⁺282 (100%) 276 (5%)

[0168] Similarly produced are also the following intermediate products:

Beispiel- 6.1 6.2 6.3 Nr. Aus- 46% 32% 39% beute Masse EI: ESI: ESI: M⁺267 (3%) MH⁺ 308 MH⁺ 296 223 (100%) (100%) (100%) 132 (27%) 306 (71%)294 (73%) 268 (31%) 217 (4%)

Beispiel-Nr. 6.4 6.5 Ausbeute 36% 50% Masse EI: ESI: M+ 281 MH⁺ 310 (3%)(100%) 223 (100%) 308 (87%) 114 (38%) 298 (9%)

Beispiel-Nr. 6.6 6.7 6.8 Ausbeute 40% 20% 35% Masse EI: Cl: ESI: M⁺ 358M⁺ 310 (100%) MH⁺ 294 (100%) 308 (84%) (28%) 356 (97%) 130 (54%) 296(36%) 277 (29%) 210 (100%)

Beispiel-Nr. 6.9 6.10 Ausbeute 29% 67% Masse ESI: ESI: MH⁺ 308 MH+ 310(87%) (28%) 312 (100%) 310 123 (24%) (38%) 210 (100%)

[0169] Subjects of this invention are thus also compounds of generalformula Ia

[0170] in which

[0171] D stands for halogen, and X, R¹, and R² have the meanings thatare indicated in general formula (1).

[0172] Those intermediate products of general formula Ia, in which Dstands for chlorine and X, R¹ and R² have the meanings that areindicated in the general formula, are especially valuable. InhibitionIC₅₀ Beispiel [nM] Proliferation IC₅₀ [μM] Sw Nummer CDK2/CycE MCF7 H460HCT116 DU145 (g/l) 37 70 4 0.006 6 70 4 6 0.008 16 300 3 24 400 5 35120 >10 23 180 3 38 80 >10 43 200 6 0.04 42 2000 0.043 50 150 5 90 100.043 54 100 1, 1 0.0015

[0173] No. Structure Name 24

5-Bromo-N4-2-propynyl-N2-(4- trifluoromethylthiophenyl)-2,4-pyrimidinediamine 35

5-Bromo-N4-2-propynyl-N2-(3- trifluoromethylthiophenyl)-2,4-pyrimidinediamine 37

N-[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]- indazol-5-amine 38

N-[5-Bromo-4-(2-propynylamino)-2-pyrimidinyl]- benzothiazole-5-amine 42

4-[[5-Fluoro-4-(2-propynyloxy)-2-pyrimidinyl]amino]- phenol 43

4-[[5-Chloro-4-(2-propynyloxy)-2-pyrimidinyl]amino]- phenol 50

1-[4-[(5-Bromo-4-(2-propynylamino)-2- pyrimidinyl)amino]phenyl]-ethanone54

1-[4-[(5-Iodo-4-(2-propynylamino)-2- pyrimidinyl)amino]phenyl]-ethanone70

1-[4-[(5-Ethyl-4-(2-propynylamino)-2- pyrimidinyl)amino]phenyl]-ethanone81

1-[4-[(5-Bromo-4-(2-propynylamino)-2- pyrimidinyl)amino]phenyl]-ethanol82

1-[4-[(5-Bromo-4-(2-propynyloxy)-2- pyrimidinyl)amino]phenyl]-ethanol

[0174] The invention thus relates in addition to pharmaceutical agentsthat comprise a compound of general formula I

[0175] in which

[0176] R¹ stands for halogen or C₁-C₃-alkyl

[0177] X stands for oxygen or —NH,

[0178] A stands for hydrogen

[0179] B stands for hydroxy, —CO-alkyl-R⁷, —S—CHF₂,—S—(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —S—CF₃, or —CH—(OH)—CH₃, or

[0180] A and B, independently of one another, can form a group

[0181] R², R³, R⁴, R⁷ and R⁸ have the meanings that are indicated ingeneral formula I, as well as isomers, diastereomers, enantiomers andsalts thereof.

[0182] The agents according to the invention can also be used fortreating cancer, auto-immune diseases, cardiovascular diseases,chemotherapy agent-induced alopecia and mucositis, infectious diseases,nephrological diseases, chronic and acute neurodegenerative diseases andviral infections, whereby cancer is defined as solid tumors andleukemia; auto-immune diseases are defined as psoriasis, alopecia andmultiple sclerosis; cardiovascular diseases are defined as stenoses,arterioscleroses and restenoses; infectious diseases are defined asdiseases that are caused by unicellular parasites; nephrologicaldiseases are defined as glomerulonephritis; chronic neurodegenerativediseases are defined as Huntington's disease, amyotrophic lateralsclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease;acute neurodegenerative diseases are defined as ischemias of the brainand neurotraumas; and viral infections are defined as cytomegalicinfections, herpes, hepatitis B or C, and HIV diseases.

[0183] The following examples describe the biological action of thecompounds according to the invention without limiting the invention tothese examples.

EXAMPLE 1

[0184] CDK2/CycE Kinase Assay

[0185] Recombinant CDK2- and CycE-GST-fusion proteins, purified frombaculovirus-infected insect cells (Sf9), were obtained by Dr. DieterMarmé, Klinik für Tumorbiologie [Clinic for Tumor Biology], Freiburg.Histone IIIS, which was used as a kinase substrate, was purchased by theSigma Company.

[0186] CDK2/CycE (50 ng/measuring point) was incubated for 15 minutes at22° C. in the presence of various concentrations of test substances (0μm, as well as within the range of 0.01-100 μm) in assay buffer [50 mmolof tris/HCl pH 8.0, 10 mmol of MgCl₂, 0.1 mmol of Na ortho-vanadate, 1.0mmol of dithiothreitol, 0.5 μm of adenosine triphosphate (ATP), 10μg/measuring point of histone IIIS, 0.2 μCi/measuring point of ³³P-gammaATP, 0.05% NP40, 12.5% dimethyl sulfoxide]. The reaction was stopped byadding EDTA solution (250 mmol, pH 8.0, 14 μl/measuring point).

[0187] From each reaction batch, 10 μl was applied to P30 filter strips(Wallac Company), and non-incorporated ³³P-ATP was removed by subjectingthe filter strips to three washing cycles for 10 minutes each in 0.5%phosphoric acid. After the filter strips were dried for one hour at 70°C., the filter strips were covered with scintillator strips (MeltiLex™A, Wallac Company) and baked for one hour at 90° C. The amount ofincorporated ³³P (substrate phosphorylation) was determined byscintillation measurement in a gamma-radiation measuring device(Wallac).

EXAMPLE 2

[0188] Proliferation Assay

[0189] Cultivated human tumor cells (as indicated) were flattened out ata density of 5000 cells/measuring point in a 96-hole multititer plate in200 μl of the corresponding growth medium. After 24 hours, the cells ofone plate (zero-point plate) were colored with crystal violet (seebelow), while the medium of the other plates was replaced by freshculture medium (200 μl), to which the test substances were added atvarious concentrations (0 μm, as well as in the range of 0.01-30 μm; thefinal concentration of the solvent dimethyl sulfoxide was 0.5%). Thecells were incubated for 4 days in the presence of test substances. Thecell proliferation was determined by coloring the cells with crystalviolet: the cells were fixed by adding 20 μl/measuring point of a 11%glutaric aldehyde solution for 15 minutes at room temperature. Afterthree washing cycles of the fixed cells with water, the plates weredried at room temperature. The cells were colored by adding 100μl/measuring point of a 0.1% crystal violet solution (pH was set at 3 byadding acetic acid). After three washing cycles of the colored cellswith water, the plates were dried at room temperature. The dye wasdissolved by adding 100 μl/measuring point of a 10% acetic acidsolution. The extinction was determined by photometry at a wavelength of595 nm. The change of cell growth, in percent, was calculated bystandardization of the measured values to the extinction values of thezero-point plate (=0%) and the extinction of the untreated (0 μm) cells(=100%).

[0190] The results of Examples 1 and 2 are cited in the followingtables.

[0191] [Key to Subsequent Tables:]

[0192] Beispiel Nummer=Example Number Inhibition IC₅₀ Beispiel [nM]Proliferation IC₅₀ [μM] Sw Nummer CDK2/CycE MCF7 H460 HCT116 DU145 (g/l)22 40 1, 2 1, 5 1, 5 1, 5 0.003 37 70 4 0.006 6 70 4 6 0.008 40 20 1 3 39 0.002 51 70 8 20 60 4 21 400 2 1 300 8 2 700 16 300 3 24 400 5 26 3003 35 120 >10 23 180 3 11 6 0, 2 0, 5 0, 3 0, 2 38 80 >10 34 1800 10 4 0,2 0, 5 0, 5 0, 5 12 400 4 25 70 1, 2 1, 5 1, 1 1, 2 0.017 9 7 0, 9 3 3 76 0, 7 1, 5 1, 2 0, 5 0.028 31 800 7 0.0023 14 200 3 0.013 18 2000 0.0393 200 8 0.039 19 800 >10 0.041 13 2000 >10 17 1000 >10 0.04 4 40 8 0.04215 300 >10 0.024 8 <10 4 0.007 43 200 6 0.04 36 30 0, 4 0, 6 0, 5 0, 60.018 27 >10000 42 2000 0.043 39 300 0.0016 44 8 1, 2 0, 4 0, 4 0, 30.005 45 10 2 1, 7 1, 2 0, 5 0.0094 50 150 5 90 10 0.043 46 7 2 0.006952 200 0, 2 1, 6 1, 2 2 0.0005 53 300 1, 6 0.026 54 100 1, 1 0.0015 4712 0, 7 1, 8 1, 3 0, 9 56 80 4 0.023 49 50 >10 0.044 48 4 0, 2 1 0, 4 0,3 0.042 96 400 0.0005 98 2000 85 2000 0.001 84 400 0.0005 86 3000 87 2500, 8 0.003 22 40 1, 2 1, 5 1, 5 1, 5 0.003 37 70 4 0.006 6 70 4 6 0.00816 300 3 24 400 5 35 120 >10 23 180 3 38 80 >10 43 200 6 0.04 42 20000.043 50 150 5 90 10 0.043 54 100 1, 1 0.0015

[0193] Proof of Superiority of the Compounds According to the InventionCompared to the Known Compounds

[0194] To prove the superiority of the compounds according to theinvention compared to the known compounds, the compounds according tothe invention were compared to known reference compounds andstructurally-similar known compounds in the enzyme test. The result iscited in the following table: CDK2/CycE MCF-7 Löslichkeit Beispiel-Nr.R² A IC₅₀ [nM] IC₅₀ [μM] (g/l)

CH(C₃H₇)—CH₂—OH— —SO₂—N—(CH₂)₂—OH 4 0.2 0.042

CH(CH₂OH)₂ SO₂NH₂ 7 0.9 0.009

Propargyl- NH— SO₂NH₂ 6 0.2

7000 30

1500 8

1800 6

90 1.2

10 2

190

[0195] It can be seen from the results of the table that both in theenzyme test and in the cell test, the compounds according to theinvention have significantly higher activities in the enzyme and in theMCF-7 cells than the compounds that are known from the prior art. Thecompounds according to the invention are thus far superior to the knowncompounds.

1. Compounds of general formula I

in which R¹ stands for hydrogen, halogen, C₁-C₆-alkyl, nitro, or for thegroup —COR⁵, —OCF₃, —(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃, R² stands forC₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl orfor C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkylthat is substituted in one or more places in the same way or differentlywith hydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano,C₁-6-alkyl, —NH—(CH₂)_(n)-C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl,C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,—NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl),C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl,heteroaryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵,—(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl,C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and—(CH₂)_(n)-heteroaryl itself optionally can be substituted in one ormore places in the same way or differently with halogen, hydroxy,C₁-C₆-alkyl, C₁-C₆-alkoxy, heteroaryl, benzoxy or with the group —CF₃ or—OCF₃, and the ring of the C₃-C₁₀-cycloalkyl and the C₁-C₁₀-alkyloptionally can be interrupted by one or more nitrogen, oxygen and/orsulfur atoms and/or can be interrupted by one or more ═C═O groups in thering and/or optionally one or more possible double bonds can becontained in the ring, or R² stands for the group

X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or for—OC₃-C₁₀-cycloalkyl, which can be substituted in one or more places inthe same way or differently with a heteroaromatic compound, or X and R²together form a C₃-C₁₀-cycloalkyl ring, which optionally can contain oneor more heteroatoms and optionally can be substituted in one or moreplaces with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, A and B, ineach case independently of one another, stand for hydrogen, hydroxy,C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —SR⁷, —S(O)R⁷, —SO₂R⁷,—NHSO₂R⁷, —CH(OH)R⁷, —CR⁷(OH)—R⁷, C₁-C₆-alkylP(O)OR³ OR⁴ or —COR⁷, orfor

or A and B together form a C₃-C₁₀-cycloalkyl ring that optionally can beinterrupted by one or more nitrogen, oxygen and/or sulfur atoms and/orcan be interrupted by one or more ═C═O or ═SO₂ groups in the ring and/oroptionally one or more possible double bonds can be contained in thering, and the C₃-C₁₀-cycloalkyl ring optionally can be substituted inone or more places in the same way or differently with hydroxy, halogen,C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₃-C₁₀-cycloalkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl,—N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂R⁷, C₁-C₆-alkanoyl, —CONR³R⁴,—COR⁵, C₁-C₆-alkoxyOAc, phenyl or with the group R⁶, whereby the phenylitself optionally can be substituted in one or more places in the sameway or differently with halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy orwith the group —CF₃ or —OCF₃, R³ and R⁴, in each case independently ofone another, stand for hydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl,C₁-C₆-alkoxy, C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy,hydroxy-C₁-C₆-alkyl, dihydroxy-C₁-C₆-alkyl, heteroaryl,heterocyclo-C₃-C₁₀-alkyl, heteroaryl-C₁-C₃-alkyl,C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionally substituted with cyano,or for C₁-C₆-alkyl that is optionally substituted in one or more placesin the same way or differently with phenyl, pyridyl, phenyloxy,C₃-C₆-cycloalkyl, C₁-C₆-alkyl or C₁-C₆-alkoxy, whereby the phenyl itselfcan be substituted in one or more places in the same way or differentlywith halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴, orfor the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴, or R³ and R⁴ togetherform a C₃-C₁₀-cycloalkyl ring that optionally can be interrupted by oneor more nitrogen, oxygen and/or sulfur atoms and/or can be interruptedby one or more ═C═O groups in the ring and/or optionally one or morepossible double bonds can be contained in the ring, R⁵ stands forhydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, benzoxy, C₁-C₆-alkylthioor C₁-C₆-alkoxy, R⁶ stands for a heteroaryl or C₃-C₁₀-cycloalkyl ring,whereby the ring has the above-indicated meaning, R⁷ stands for halogen,hydroxy, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₃-C₁₀-cycloalkyl, with the above-indicated meaning, or for the group—NR³R⁴, or for a C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl orC₃-C₇-cycloalkyl that is substituted in one or more places in the sameway or differently with hydroxy, C₁-C₆-alkoxy, halogen, phenyl, —NR³R⁴or phenyl, which itself can be substituted in one or more places in thesame way or differently with halogen, hydroxy, C₁-C₆-alkyl,C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, or R⁷ stands forphenyl, which itself can be substituted in one or more places in thesame way or differently with halogen, hydroxy, C₁-C₆-alkyl orC₁-C₆-alkoxy, halo-C₁-C₆-alkyl, or halo-C₁-C₆-alkoxy, R⁸, R⁹ and R¹⁰, ineach case independently of one another, stand for hydrogen, hydroxy,C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, C₃-C₁₀-cycloalkyl, aryl,heteroaryl or for C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl orC₃-C₁₀-cycloalkyl that is optionally substituted in one or more placesin the same way or differently with hydroxy, halogen, C₁-C₆-alkoxy,C₁-C₆-alkylthio, amino, cyano, C₁-C₆-alkyl,—NH—(CH₂)_(n)—C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl, C₁-C₆-hydroxyalkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, —NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,—SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl), C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵,C₁-C₆-alkylOAc, carboxy, aryl, heteroaryl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵, —(CH₂)_(n)PO₃(R⁵)₂ or withthe group —R⁶ or —NR³R⁴, and the phenyl, C₃-C₁₀-cycloalkyl, aryl,heteroaryl, —(CH₂)_(n)-aryl and —(CH₂)_(n)-heteroaryl itself optionallycan be substituted in one or more places in the same way or differentlywith halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —CF₃or —OCF₃, and the ring of C₃-C₁₀-cycloalkyl and the C₁-C₁₀-alkyloptionally can be interrupted by one or more nitrogen, oxygen and/orsulfur atoms and/or can be interrupted by one or more ═C═O groups in thering and/or optionally one or more possible double bonds can becontained in the ring, and n stands for 0-6, as well as isomers,diastereomers, enantiomers and salts thereof.
 2. Compounds of generalformula I, according to claim 1, in which R¹ stands for hydrogen,halogen, C₁-C₆-alkyl, nitro, or for the group —COR⁵, —OCF₃,—(CH₂)_(n)R⁵, —S—CF₃ or —SO₂CF₃, R² stands for C₁-C₁₀-alkyl,C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl or forC₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkinyl, or C₃-C₁₀-cycloalkyl thatis substituted in one or more places in the same way or differently withhydroxy, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, amino, cyano,C₁-C₆-alkyl, —NH—(CH₂)_(n)-C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkyl,C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl,—NHC₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —SO(C₁-C₆-alkyl), —SO₂(C₁-C₆-alkyl),C₁-C₆-alkanoyl, —CONR³R⁴, —COR⁵, C₁-C₆-alkylOAc, carboxy, aryl,heteroaryl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, phenyl-(CH₂)_(n)—R⁵,—(CH₂)_(n)PO₃(R⁵)₂ or with the group —R⁶ or —NR³R⁴, and the phenyl,C₃-C₁₀-cycloalkyl, aryl, heteroaryl, —(CH₂)_(n)-aryl and—(CH₂)_(n)-heteroaryl itself optionally can be substituted in one ormore places in the same way or differently with halogen, hydroxy,C₁-C₆-alkyl, C₁-C₆-alkoxy, heteroaryl, benzoxy or with the group —CF₃ or—OCF₃, and the ring of the C₃-C₁₀-cycloalkyl and the C₁-C₁₀-alkyloptionally can be interrupted by one or more nitrogen, oxygen and/orsulfur atoms and/or can be interrupted by one or more ═C═O groups in thering and/or optionally one or more possible double bonds can becontained in the ring, or R² stands for the group

X stands for oxygen or for the group —NH—, —N(C₁-C₃-alkyl) or for—OC₃—C₁₀-cycloalkyl, which can be substituted in one or more places inthe same way or differently with a heteroaromatic compound, or X and R²together form a C₃-C₁₀-cycloalkyl ring, which optionally can contain oneor more heteroatoms and optionally can be substituted in one or moreplaces with hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, A and B, ineach case independently of one another, stand for hydrogen, hydroxy,C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —S—CH₃, —SO₂—C₂H₄—OH,—CO—CH₃, —S—CHF₂, —S—(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —CH₂P(O)OR³OR⁴, —S—CF₃,—SO—CH₃, —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴, —SO₂—NR³R⁴, —SO₂R⁷,—CH—(OH)—CH₃ or for

A and B together can form a group

R³ and R⁴, in each case independently of one another, stand forhydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy,C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl,dihydroxy-C₁-C₆-alkyl, heteroaryl, heterocyclo-C₃-C₁₀-alkyl,heteroaryl-C₁-C₃-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl optionallysubstituted with cyano, or for C₁-C₆-alkyl that is optionallysubstituted in one or more places in the same way or differently withphenyl, pyridyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl orC₁-C₆-alkoxy, whereby the phenyl itself can be substituted in one ormore places in the same way or differently with halogen,trifluoromethyl, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴,or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴ or for

 which optionally can be substituted with C₁-C₆-alkyl, R⁵ stands forhydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, benzoxy, C₁-C₆-alkylthioor C₁-C₆-alkoxy, R⁶ stands for the group

R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, —C₂H₄OH, —NR³R⁴, orthe group

R⁸, R⁹ and R¹⁰, in each case independently of one another, stand forhydrogen, hydroxy, C₁-C₆-alkyl, C₃-C₆-cycloalkyl or for the group

 and n stands for 0-6, as well as isomers, enantiomers, diastereomers,and salts thereof.
 3. Compounds of general formula I, according toclaims 1 and 2, in which R² stands for hydrogen, halogen, C₁-C₃-alkyl,or for the group —(CH₂)_(n)R⁵, R¹ stands for —CH(CH₃)—(CH₂)_(n)—R⁵,—CH—(CH₂OH)₂, —(CH₂)_(n)R⁷, —CH(C₃H₇)—(CH₂)_(n)—R5,—CH(C₂H₅)—(CH₂)_(n)—R⁵, —CH₂—CN,—CH(CH₃)COCH₃,—CH(CH₃)—C(OH)(CH₃)₂,—CH(CH(OH)CH₃)OCH₃, —CH(C₂H₅)CO—R⁵, C₂-C₄-alkinyl,—(CH₂)_(n)—COR⁵, —(CH₂)_(n)—CO—C₁-C₆-alkyl,—(CH₂)_(n)—C(OH)(CH₃)-phenyl, —CH(CH₃)—C(CH₃)—R⁵,—CH(CH₃)—C(CH₃)(C₂H₅)—R⁵, —CH(OCH₃)—CH₂—R⁵, —CH₂—CH(OH)—R⁵,—CH(OCH₃)—CHR⁵—CH₃, —CH(CH₃)—CH(OH)—CH₂—CH═CH₂,—CH(C₂H₅)—CH(OH)—(CH₂)_(n)—CH₃, —CH(CH₃)—CH(OH)—(CH₂)_(n)—CH₃,—CH(CH₃)—CH(OH)—CH(CH₃)₂, (CH₂OAC)₂, —(CH₂)_(n)—R⁶,—(CH₂)_(n)—(CF₂)_(n)—CF₃, —CH(CH₂)_(n)—R⁵)₂, —CH(CH₃)—CO—NH₂,—CH(CH₂OH)-phenyl, —CH(CH₂OH)—CH(OH)—(CH₂)_(n)R⁵,—CH(CH₂OH)—CH(OH)-phenyl, —CH(CH₂OH)—C₂H₄—R⁵,—(CH₂)_(n)—C≡C—C(CH₃)═CH—COR⁵, —CH(Ph)—(CH₂)_(n)—R⁵, —(CH₂)_(n)—COR⁵,—(CH₂)_(n)PO₃(R⁵)₂, —(CH₂)_(n)—COR⁵, —CH((CH₂)_(n)OR⁵)CO—R⁵,—(CH₂)_(n)CONHCH((CH₂)_(n)R⁵)₂, —(CH₂)_(n)NH—COR⁵,—CH(CH₂)_(n)R⁵—(CH₂)_(n)C₃-C₁₀-cycloalkyl, —(CH₂)_(n)—C₃—C₁₀-cycloalkyl,C₃-C₁₀-cycloalkyl; C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl,—(CH₂)_(n)—O—(CH₂)_(n)—R⁵, —(CH₂)_(n)—NR³R⁴ that is optionallysubstituted in one or more places in the same way or differently withhydroxy, C₁-C₆-alkyl or the group —COONH(CH₂)_(n)CH₃ or —NR³R⁴,—CH(C₃H₇)—(CH₂)_(n)—OC(O)—(CH₂)_(n)—CH₃, —(CH₂)_(n)—R⁵,—C(CH₃)₂—(CH₂)_(n)—R⁵, —C(CH₂)_(n)(CH₃)—(CH₂)_(n)R⁵,—C(CH₂)_(n)—(CH₂)_(n)R⁵, —CH(t-butyl)—(CH₂)_(n)—R⁵,—CCH₃(C₃H₇)—(CH₂)_(n)R⁵, —CH(C₃H₇)—(CH₂)_(n)—R⁵, —CH(C₃H₇)—COR⁵,—CH(C₃H₇)—(CH₂)_(n)—OC(O)—NH—Ph, —CH((CH₂)_(n)(C₃H₇))—(CH₂)_(n)R⁵,—CH(C₃H₇)—(CH₂)_(n)—OC(O)—NH—Ph(OR⁵)₃, —NR³R⁴, —NH—(CH₂)_(n)—NR³R⁴,R—(CH₂)_(n)—C*H—CH(R⁵)—(CH₂)_(n)—R⁵, —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CO—R⁵,—OC(O)NH—C₁-C₆-alkyl or —(CH₂)_(n)—CO—NH—(CH₂)_(n)—CH—((CH₂)_(n)R⁵)₂, orfor C₃-C₁₀-cycloalkyl, which is substituted with the group

 or for the group X stands for oxygen or for the group —NH—,—N(C₁-C₃-alkyl) or

or R² stands for the group

or X and R² together form a group

A and B, in each case independently of one another, stand for hydrogen,hydroxy, C₁-C₃-alkyl, C₁-C₆-alkoxy or for the group —S—CH₃,—SO₂—C₂H₄—OH, —CO—CH₃, —S—CHF₂, —S(CH₂)_(n)CH(OH)CH₂N—R³R⁴,—CH₂PO(OC₂H₅)₂, —S—CF₃, —SO—CH₃, —SO₂CF₃, —SO₂—(CH₂)_(n)—N—R³R⁴,—SO₂—NR³R⁴, —SO₂R⁷, —CH(OH)—CH₃, —COOH, —CH((CH₂)_(n)R⁵)₂, —(CH₂)_(n)R⁵,—COO—C₁-C₆-alkyl, —CONR³R⁴ or for

A and B together can form a group

or R³ and R⁴, in each case independently of one another, stand forhydrogen, phenyl, benzyloxy, C₁-C₁₂-alkyl, C₁-C₆-alkoxy,C₂-C₄-alkenyloxy, C₃-C₆-cycloalkyl, hydroxy, hydroxy-C₁-C₆-alkyl,dihydroxy-C₁-C₆-alkyl, heteroaryl, heterocyclo-C₃-C₁₀-alkyl,heteroaryl-C₁-C₃-alkyl, C₃-C₆-cycloalkyl-C₁-C₃-alkyl that is optionallysubstituted with cyano, or for C₁-C₆-alkyl that is optionallysubstituted in one or more places in the same way or differently withphenyl, pyridyl, phenyloxy, C₃-C₆-cycloalkyl, C₁-C₆-alkyl orC₁-C₆-alkoxy, whereby the phenyl itself can be substituted in one ormore places in the same way or differently with halogen,trifluoromethyl, C₁-C₆-alkyl, C₁-C₆-alkoxy or with the group —SO₂NR³R⁴,or for the group —(CH₂)_(n)NR³R⁴, —CNHNH₂ or —NR³R⁴ or for

or  which optionally can be substituted with C₁-C₆-alkyl, R⁵ stands forhydroxy, phenyl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, benzoxy, C₁-C₆-alkylthioor C₁-C₆-alkoxy, R⁶ stands for the group

R⁷ stands for halogen, hydroxy, phenyl, C₁-C₆-alkyl, —(CH₂)_(n)OH,—NR³R⁴ or the group

R⁸, R⁹ and R¹⁰ stand for hydrogen, hydroxy, C₁-C₆-alkyl or for the group—(CH₂)_(n)—COOH, and n stands for 0-6, as well as isomers,diastereomers, enantiomers and salts thereof.
 4. Use of the compound ofgeneral formula Ia

In which D stands for halogen, and X, R¹, and R² have the meanings thatare indicated in general formula (I), as intermediate products for theproduction of the compound of general formula I.
 5. Use of the compoundsof general formula Ia, according to claim 4, in which D stands forchlorine and X, R¹ and R² have the meanings that are indicated in thegeneral formula.
 6. Pharmaceutical agents that comprise a compound ofgeneral formula I in which R¹ stands for halogen or C₁-C₃-alkyl X standsfor oxygen or —NH, A stands for hydrogen B stands for hydroxy,—CO-alkyl-R⁷, —S—CHF₂, —S—(CH₂)_(n)CH(OH)CH₂N—R³R⁴, —S—CF₃, or—CH—(OH)—CH₃, or A and B, independently of one another, can form a group

R², R³, R⁴, R⁷ and R⁸ have the meanings that are indicated in generalformula I, as well as isomers, diastereomers, enantiomers and saltsthereof.
 7. Use of the compounds of general formula I, according toclaims 1 to 3, for the production of a pharmaceutical agent for treatingcancer, auto-immune diseases, chemotherapy agent-induced alopecia andmucositis, cardiovascular diseases, infectious diseases, nephrologicaldiseases, chronic and acute neurodegenerative diseases and viralinfections.
 8. Use according to claim 7, wherein cancer is defined assolid tumors and leukemia; auto-immune diseases are defined aspsoriasis, alopecia and multiple sclerosis; cardiovascular diseases aredefined as stenoses, arterioscleroses and restenoses; infectiousdiseases are defined as diseases that are caused by unicellularparasites; nephrological diseases are defined as glomerulonephritis;chronic neurodegenerative diseases are defined as Huntington's disease,amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia andAlzheimer's disease; acute neurodegenerative diseases are defined asischemias of the brain and neurotraumas; and viral infections aredefined as cytomegalic infections, herpes, hepatitis B and C, and HIVdiseases.
 9. Pharmaceutical agents that contain at least one compoundaccording to claims 1 to
 3. 10. Pharmaceutical agent according to claim9 for treating cancer, auto-immune diseases, cardiovascular diseases,infectious diseases, nephrological diseases, neurodegenerative diseasesand viral infections.
 11. Compounds according to claims 1 to 3 andpharmaceutical agents according to claims 6 to 7, with suitableformulation substances and vehicles.
 12. Use of the compounds of generalformula I and the pharmaceutical agents, according to claims 1 to 3 and6, as inhibitors of the cyclin-dependent kinases.
 13. Use according toclaim 12, wherein the kinase is CDK1, CDK2, CDK3, CDK4, CDK5, CDK6,CDK7, CDK8 or CDK9.
 14. Use of the compounds of general formula I andthe pharmaceutical agents, according to claims 1 to 3 and 6, asinhibitors of the glycogen-synthase-kinase (GSK-3β).
 15. Use of thecompounds of general formula I, according to claims 1 to 3, in the formof a pharmaceutical preparation for enteral, parenteral and oraladministration.
 16. Use of the agent according to claim 6, in the formof a preparation for enteral, parenteral and oral administration.